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1
Tyagi, Suresh C., Lane M. Smiley, and Vibhas S. Mujumdar. "Homocyst(e)ine impairs endocardial endothelial function." Canadian Journal of Physiology and Pharmacology 77, no. 12 (November 15, 1999): 950–57. http://dx.doi.org/10.1139/y99-102.
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Homocyst(e)ine injured vascular endothelium and modulated endothelial-dependent vascular function. Endothelium plays an analogous role in both the vessel and the endocardium. Therefore, we hypothesized that homocyst(e)ine modulated endocardial endothelium (EE) dependent cardiac function. The ex vivo cardiac rings from normal male Wistar-Kyoto rats were prepared. The contractile responses of left and right ventricular rings were measured in an isometric myobath, using different concentrations of CaCl2. The response was higher in the left ventricle than right ventricle and was elevated in endocardium without endothelium. The half effective concentration (EC50) and maximum tension generated by homocyst(e)ine were 106 and 5-fold lower than endothelin (ET) and angiotensin II (AII), respectively. However, in endothelial-denuded endocardium, homocyst(e)ine response was significantly increased (p < 0.005, compared with intact endothelium) and equal to the response to ET and AII. To determine the physiological significance of ET, AII, homocyst(e)ine, and endothelial nitric oxide in EE function, cardiac rings were pretreated with AII (10-10 M) or ET (10-13 M) and then treated with homocyst(e)ine (10-8 M). Results suggested that at these concentrations AII, ET, or homocyst(e)ine alone had no effect on cardiac contraction. However, in the presence of 10-10 M AII or 10-13 M ET, the cardiac contraction to homocyst(e)ine (10-8 M) was significantly enhanced (p < 0.01, compared with without pretreatment) and further increased in the endocardium without endothelium. The pretreatment of cardiac ring with the inhibitor of nitric oxide, Nω-nitro-L-arginine methyl ester (L-NAME), increased contractile response to homocyst(e)ine. These results suggested that homocyst(e)ine impaired EE-dependent cardiac function and acted synergistically with AII and ET in enhancing the cardiac contraction.Key words: endocardial remodeling, homocyst(e)ine, contraction, endothelin, angiotensin, endothelial-derived relaxing factor (EDRF), Nω-nitro-L-arginine methyl ester (L-NAME), endothelial dysfunction, ex vivo cardiac function, heart failure.
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O. R. Luchko. "A relation of the indices of systemic inflammation and endothelial dysfunction in patients with chronic pyelonephritis and arterial hypertension." Bukovinian Medical Herald 17, no. 1 (65) (February 2, 2013): 59–63. http://dx.doi.org/10.24061/2413-0737.xvii.1.65.2013.15.
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The dynamics of the indicators of systemic inflammation (C-reactive protein - CRP, tumor necrosis factoralpha – TNF-α, IL-1 – IL-1, IL-6 – IL-6, soluble cell-cell adhesion molecule – sICAM-1) and endothelial dysfunction (pulse blood pressure – PBP, aortic stiffness index – ASI, the thickness of intima-media complex – TIMC, the velocity of the pulse wave propagation – VPWP, CAVI, endothelium dependent vasodilatation – EDVD and endothelium independent vasodilatation – EIVD, endothelin-1 – ET-1) in 105 patients with chronic pyelonephritis (CPN) and arterial hypertension (AH), depending on the glomerular filtration rate (GFR). 91 (86,67 %) patients have demonstrated the signs of a systemic inflammation which intensify with decreased GFR <90 ml/min. Reduced resilient- elastic properties of the arteries with increased ASI, VPW, CAVI, the levels of endothelinemia and a decrease of EDVD and EIVD was noted in 87 (82,86 %) patients with CPN and AH. The authors have observed a correlation between the indicators of the systemic inflammatory response (CRP, TNF-α, IL-1β, IL-6, sICAM-1) and the markers of the endothelial dysfunction (EDVD, EIVD, CAVI) in the group mentioned above which increases with a decrease of the glomerular filtration rate which should be considered, when treating such patients.
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Hao, Ying, Zhuang Wang, Francis Frimpong, and Xingjuan Chen. "Calcium–Permeable Channels and Endothelial Dysfunction in Acute Lung Injury." Current Issues in Molecular Biology 44, no. 5 (May 16, 2022): 2217–29. http://dx.doi.org/10.3390/cimb44050150.
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The increased permeability of the lung microvascular endothelium is one critical initiation of acute lung injury (ALI). The disruption of vascular-endothelium integrity results in leakiness of the endothelial barrier and accumulation of protein-rich fluid in the alveoli. During ALI, increased endothelial-cell (EC) permeability is always companied by high frequency and amplitude of cytosolic Ca2+ oscillations. Mechanistically, cytosolic calcium oscillations include calcium release from internal stores and calcium entry via channels located in the cell membrane. Recently, numerous publications have shown substantial evidence that calcium-permeable channels play an important role in maintaining the integrity of the endothelium barrier function of the vessel wall in ALI. These novel endothelial signaling pathways are future targets for the treatment of lung injury. This short review focuses on the up-to-date research and provide insight into the contribution of calcium influx via ion channels to the disruption of lung microvascular endothelial-barrier function during ALI.
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Lam, Chen-Fuh, Yen-Chin Liu, Jen-Kuo Hsu, Pei-An Yeh, Ting-Ya Su, Chien-Chi Huang, Ming-Wei Lin, Ping-Ching Wu, Pei-Jung Chang, and Yu-Chuan Tsai. "Autologous Transplantation of Endothelial Progenitor Cells Attenuates Acute Lung Injury in Rabbits." Anesthesiology 108, no. 3 (March 1, 2008): 392–401. http://dx.doi.org/10.1097/aln.0b013e318164ca64.
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Background Acute lung injury (ALI) and end-stage acute respiratory distress syndrome (ARDS) are among the most common causes of death in intensive care units. Activation and damage of pulmonary endothelium is the hallmark of ALI/ARDS. Recent studies have demonstrated the importance of circulating endothelial progenitor cells (EPCs) in maintaining normal endothelial function as well as endothelial repairing after vascular injury. Here, the authors present the first study demonstrating the therapeutic potential of EPCs in a rabbit model of ALI/ARDS. Methods Circulating EPCs were obtained from rabbits using Ficoll centrifugation. One week after culturing, ALI was induced in rabbits by oleic acid (75 mg/kg, intravenous), and autologous EPCs were transplanted intravenously. Vasomotor function of isolated pulmonary artery and degrees of lung injury were assessed 2 days later. Results Endothelial dysfunction in the pulmonary artery was significantly attenuated in rabbits treated with EPCs, whereas the endothelium-independent relaxation responses were not different. Expression of inducible nitric oxide synthase was suppressed in the pulmonary artery of EPC-treated animals. Infiltration of leukocytes in the lung parenchyma was significantly reduced after EPC transplantation. EPCs also decreased water content, hyaline membrane formation, and hemorrhage in lungs. Conclusion The authors demonstrated that autologous transplantation of EPCs preserves pulmonary endothelial function and maintains the integrity of pulmonary alveolar-capillary barrier. Transplantation of EPCs can be a novel cell-based, endothelium-targeted therapeutic strategy for prevention and treatment of ALI/ARDS.
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Vorob’eva, Nadezda A., Alena I. Vorob’eva, and Anastasiya A. Marusiy. "Risk of Endothelial Dysfunction and Total Antioxidant Capacity in Seafarers During an Arctic Voyage." Journal of Medical and Biological Research, no. 2 (May 9, 2021): 192–200. http://dx.doi.org/10.37482/2687-1491-z057.
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Among other areas of research, clinical medicine studies the adaptation mechanisms of the vascular endothelium to the extreme conditions of the Arctic. This paper dwells on the possible relationship of the development of endothelial dysfunction and the antioxidant system with modifiable risk factors during a short translatitudinal voyage in the Arctic. The study involved 32 crew members of the research vessel Mikhail Somov during the TransArctic–2019 research expedition. Venous blood sampling was carried out before the voyage at the zero point (Arkhangelsk, 64°33’N 40°32’E) and at the highest point of the expedition (Hayes Island, 80°34’N 57°41’E). Endothelin-1 concentration and serum total antioxidant capacity were determined using the enzyme-linked immunosorbent assay. We found statistically significant differences (Student’s t-test: t = –3.6532; df = 31; p < 0.001) in endothelin-1 concentration at the zero point (4.79 ± 2.10 pg/ml) and high point (7.02 ± 2.42 pg/ml), which indicates vasoconstriction, i.e. the first signs of the formation of vascular endothelium maladaptation. In 84.4 % of the crew members at the high point we detected high total antioxidant capacity, which can indicate compensation of antioxidant defence mechanisms. Noteworthy, serum total antioxidant capacity in smokers was statistically significantly higher than in non-smokers. Moreover, the predominance of high antioxidant activity among the crew members points to an increased oxidative load on the sailors’ body having to neutralize the excess amount of reactive oxygen species. For citation: Vorob’eva N.A., Vorob’eva A.I., Marusiy A.A. Risk of Endothelial Dysfunction and Total Antioxidant Capacity in Seafarers During an Arctic Voyage. Journal of Medical and Biological Research, 2021, vol. 9, no. 2, pp. 192–200. DOI: 10.37482/2687-1491-Z057
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Zaikina, T. S., P. G. Kravchun, D. V. Minukhina, D. V. Minukhin, D. O. Yevtushenko, and I. O. Kudrevych. "COMPREHENSIVE ASSESSMENT OF ENDOTHELIUM-DEPENDENT MEDIATORS IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION AND DIABETES MELLITUS TYPE 2." Problems of Endocrine Pathology 76, no. 2 (June 10, 2021): 14–18. http://dx.doi.org/10.21856/j-pep.2021.2.02.
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The aim of study is to evaluate the levels of endothelium-dependent mediators: endothelial nitric-oxide synthase (NOS), plasminogen activator inhibitor-1 (PAI-1) and circulating soluble CD40 ligand (sCD40L) in patients with acute myocardial infarction (AMI) and concomitant type 2 diabetes mellitus (DM). The study included 255 patients with AMI, who were divided into two groups depending on the presence of concomitant type 2 DM: 1 group — 143 patients with concomitant type 2 DM; 2 group — 112 patients without concomitant disturbances of carbohydrate metabolism. Studied endothelial-dependent indicators were investigated using enzyme-linked immunosorbent assay. Statistical data were processed using the Mann–Whitney U-test, quantitative variables were described by the following parameters: median (Me), 25th and 75th percentiles (Q1; Q3). Analyzing the studied indicators on admission of patients to the hospital, a statistically significant decrease in NOS levels (p < 0,01), as well as an increase in PAI-1 (p < 0,01) and sCD40L (p < 0,01) in the cohort of patients with AMI and concomitant type 2 DM compared with patients without disturbances of carbohydrate metabolism. This indicates a more significant violation of endothelium-dependent vasodilation, thrombin fibrinolysis and activation of intravascular inflammation caused by comorbidity. Over the next 10 days, an increase in NOS levels, a decrease in PAI-1 and sCD40L levels were observed in patients of both groups, indicating a gradual improvement of the endothelial function. However, in patients with AMI and concomitant type 2 DM, the levels of the studied endothelium-dependent mediators continued to differ statistically even on the 10th day after acute occlusion of the coronary artery. In our opinion, this tendency is caused by the negative impact of metabolicdisorders associated with type 2 DM on the endothelium of the coronary arteries in patients with insulin resistance and, apparently, may increase the risk of complications of AMI.
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Kolosova, Irina A., Tamara Mirzapoiazova, Liliana Moreno-Vinasco, Saad Sammani, Joe G. N. Garcia, and Alexander D. Verin. "Protective effect of purinergic agonist ATPγS against acute lung injury." American Journal of Physiology-Lung Cellular and Molecular Physiology 294, no. 2 (February 2008): L319—L324. http://dx.doi.org/10.1152/ajplung.00283.2007.
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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major causes of acute respiratory failure associated with high morbidity and mortality. Although ALI/ARDS pathogenesis is only partly understood, pulmonary endothelium plays a major role by regulating lung fluid balance and pulmonary edema formation. Consequently, endothelium-targeted therapies may have beneficial effects in ALI/ARDS. Recently, attention has been given to the therapeutic potential of purinergic agonists and antagonists for the treatment of cardiovascular and pulmonary diseases. Extracellular purines (adenosine, ADP, and ATP) and pyrimidines (UDP and UTP) are important signaling molecules that mediate diverse biological effects via cell-surface P2Y receptors. We previously described ATP-induced endothelial cell (EC) barrier enhancement via a complex cell signaling and hypothesized endothelial purinoreceptors activation to exert anti-inflammatory barrier-protective effects. To test this hypothesis, we used a murine model of ALI induced by intratracheal administration of endotoxin/lipopolysaccharide (LPS) and cultured pulmonary EC. The nonhydrolyzed ATP analog ATPγS (50–100 μM final blood concentration) attenuated inflammatory response with decreased accumulation of cells (48%, P < 0.01) and proteins (57%, P < 0.01) in bronchoalveolar lavage and reduced neutrophil infiltration and extravasation of Evans blue albumin dye into lung tissue. In cell culture model, ATPγS inhibited junctional permeability induced by LPS. These findings suggest that purinergic receptor stimulation exerts a protective role against ALI by preserving integrity of endothelial cell-cell junctions.
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Dube, Shataakshi, Tejasvi Matam, Jessica Yen, Henry E. Mang, Pierre C. Dagher, Takashi Hato, and Timothy A. Sutton. "Endothelial STAT3 Modulates Protective Mechanisms in a Mouse Ischemia-Reperfusion Model of Acute Kidney Injury." Journal of Immunology Research 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/4609502.
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STAT3 is a transcriptional regulator that plays an important role in coordinating inflammation and immunity. In addition, there is a growing appreciation of the role STAT3 signaling plays in response to organ injury following diverse insults. Acute kidney injury (AKI) from ischemia-reperfusion injury is a common clinical entity with devastating consequences, and the recognition that endothelial alterations contribute to kidney dysfunction in this setting is of growing interest. Consequently, we used a mouse with a genetic deletion of Stat3 restricted to the endothelium to examine the role of STAT3 signaling in the pathophysiology of ischemic AKI. In a mouse model of ischemic AKI, the loss of endothelial STAT3 signaling significantly exacerbated kidney dysfunction, morphologic injury, and proximal tubular oxidative stress. The increased severity of ischemic AKI was associated with more robust endothelial-leukocyte adhesion and increased tissue accumulation of F4/80+ macrophages. Moreover, important proximal tubular adaptive mechanisms to injury were diminished in association with decreased tissue mRNA levels of the epithelial cell survival cytokine IL-22. In aggregate, these findings suggest that the endothelial STAT3 signaling plays an important role in limiting kidney dysfunction in ischemic AKI and that selective pharmacologic activation of endothelial STAT3 signaling could serve as a potential therapeutic target.
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Gauthier, Kathryn M., David X. Zhang, Erik M. Edwards, Blythe Holmes, and William B. Campbell. "Angiotensin II Dilates Bovine Adrenal Cortical Arterioles: Role of Endothelial Nitric Oxide." Endocrinology 146, no. 8 (August 1, 2005): 3319–24. http://dx.doi.org/10.1210/en.2005-0129.
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Abstract Adrenal steroidogenesis is modulated by humoral and neuronal factors and blood flow. Angiotensin II (AII) stimulates adrenal cortical aldosterone and cortisol production and medullary catecholamine release. However, AII regulation of adrenal vascular tone has not been characterized. We examined the effect of AII on diameters of cannulated bovine adrenal cortical arteries. Cortical arteries (average internal diameter = 230 μm) were constricted with U46619 and concentration-diameter responses to AII (10−13 to 10−8 mol/liter) were measured. In endothelium-intact arteries, AII induced dilations at low concentrations (maximum dilation = 25 ± 6% at 10−10 mol/liter) and constrictions at high concentrations (maximum constriction = 25 ± 18% at 10−8 mol/liter). AII constrictions were blocked by the angiotensin type 1 (AT1) receptor antagonist, losartan (10−6 mol/liter). AII dilations were enhanced by losartan (maximal dilation = 48 ± 8%), abolished by endothelial cell removal or N-nitro-l-arginine (L-NA, 3 × 10−5 mol/liter) and inhibited by the angiotensin type 2 (AT2) receptor antagonist, PD123319 (10−6 mol/liter, maximal dilation = 18 ± 4%). In a 4,5-diaminofluorescein diacetate nitric oxide (NO) assay of isolated cortical arteries, AII stimulated NO production, which was abolished by PD123319, L-NA, or endothelial cell removal. Western immunoblot of arterial homogenates and endothelial and zona glomerulosa cell lysates revealed 48-kD and 50-kD bands corresponding to AT1 and AT2 receptors, respectively, in all three and a 140-kD band corresponding to endothelial NO synthase in endothelial cells and arteries. Our results demonstrate that AII stimulates adrenal cortical arterial dilation through endothelial cell AT2 receptor activation and NO release and AT1 receptor-dependent constriction.
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Stanojevic, Dragana, Svetlana Apostolovic, Sonja Salinger-Martinovic, Ruzica Jankovic-Tomasevic, Danijela Djordjevic-Radojkovic, Milan Pavlovic, Tomislav Kostic, Vladan Cosic, Tatjana Ristic, and Ivana Stojanovic. "Endothelin-1 and nitric oxide in 3-year prognosis after acute myocardial infarction." Vojnosanitetski pregled 74, no. 9 (2017): 862–70. http://dx.doi.org/10.2298/vsp151029278s.
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Background/Aim. Acute myocardial infarction (AMI) is an important cause of mortality/morbidity worldwide. Biomarkers improve diagnostic and prognostic accuracy in AMI. The aim of this study was to investigate an increase of markers of endothelial dysfunction in AMI, measured on the 3rd day after the initial event and to investigate their association with short- and long-term (3-year) prognosis (outcome). Methods. The prospective study included 108 patients with AMI in the experimental group and 50 apparently healthy subjects in the control group. Endothelin-1 (ET-1) and nitric oxide degradation products (NOx) were determined. Results. The average age of the participants in the experimental group was 62 ? 10 years and 59 ? 9 years in the control group; 74.1% of the patients in experimental group were males and 68.8% in the control group. In 74.1% of the patients, ST-elevation myocardial infarction (STEMI) was diagnosed, and 25.9% of the patients presented with non-ST-elevation myocardial infarction (NSTEMI). Thirteen (5.6%) patients died during 3 years and they had significantly higher ET-1 levels compared to survivors [4.02 (2.72?5.93) vs 3.06 (2.23?3.58) pg/mL; p = 0.015]. Endothelin- 1 in 46 (42.6%) patients with composite endpoint (3- year mortality and rehospitalization) was significantly increased compared to other patients [3.14 (2.54?4.41) vs 3.05 (2.18?3.56) pg/mL; p = 0.035]. Intrahospital complications were found in 41 (48%) patients. Participants with echocardiographically detected complications (ventricular dyskinesia, left ventricular thrombus and papillary muscle rupture) had higher ET-1 levels compared to other patients [4.02 (2.78?5.57) vs 3.06 (2.29?3.66) pg/mL; p = 0.012]. Endothelin- 1 concentration above the 75th percentile (> 3.77 pg/mL) was associated with the increased risk for composite endpoint [Log Rank (?2 = 13.44; p < 0.001)]. Patients who were rehospitalized had significantly lower NOx concentration [125.5 (111.4?143.6) vs 139.3 (116.79?165.2) ?mol/L; p = 0.04]. Endothelin-1 positively correlated with high sensitivity troponin I (hsTnI), brain natriuretic peptide (BNP) and a number of leukocytes. Conclusion. Endothelin- 1 and NOx were increased on the 3rd day after AMI, and they were predictors of worse short- and long-term (3- year) prognosis (outcome). Endothelin-1 positively correlated with conventional prognostic markers in AMI.
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Димова, Евгения, and Evgeniya Dimova. "THE STATE OF VASOMOTOR ENDOTHELIAL FUNCTION IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE IN COMBINATION WITH ACUTE MYOCARDIAL INFARCTION." Bulletin physiology and pathology of respiration 1, no. 67 (March 6, 2018): 37–40. http://dx.doi.org/10.12737/article_5a9f261dc23047.85257701.
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The aim of the study is to investigate a vasomotor function of patients with COPD against the development of acute myocardial infarction (AMI) with an elevation of the ST segment of the electrocardiogram. The brachial artery reactivity was studied in 42 patients with COPD during the course of treatment in the Amur Regional Clinical Hospital. All the patients were divided into two groups: 1st group (22 patients) with COPD and AMI with an elevation of the ST segment; 2nd group (20 patients) - with moderate COPD. The control group included 15 healthy people without cardiovascular diseases and respiratory pathology. The study was done at the ultrasonic device Toshiba Aplio XG with the linear probe of 10MHz using the method by D.S.Celermajer et al. (1992). The following results were obtained: the majority of COPD patients demonstrate vasomotor endothelial dysfunction that can cause atherosclerosis; in case of COPD and AMI comorbidity an endothelial dysfunction redoubles; development of AMI coincides with the “peak” of endothelial dysfunction determined with the help of endothelium-dependent vasodilatation. The method of endothelial dysfunction determination is non-invasive and accurate to predict cardiovascular diseases in COPD patients.
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Htwe, Yu Maw, Huashan Wang, Patrick Belvitch, Lucille Meliton, Mounica Bandela, Eleftheria Letsiou, and Steven M. Dudek. "Group V Phospholipase A2 Mediates Endothelial Dysfunction and Acute Lung Injury Caused by Methicillin-Resistant Staphylococcus aureus." Cells 10, no. 7 (July 8, 2021): 1731. http://dx.doi.org/10.3390/cells10071731.
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Lung endothelial dysfunction is a key feature of acute lung injury (ALI) and clinical acute respiratory distress syndrome (ARDS). Previous studies have identified the lipid-generating enzyme, group V phospholipase A2 (gVPLA2), as a mediator of lung endothelial barrier disruption and inflammation. The current study aimed to determine the role of gVPLA2 in mediating lung endothelial responses to methicillin-resistant Staphylococcus aureus (MRSA, USA300 strain), a major cause of ALI/ARDS. In vitro studies assessed the effects of gVPLA2 inhibition on lung endothelial cell (EC) permeability after exposure to heat-killed (HK) MRSA. In vivo studies assessed the effects of intratracheal live or HK-MRSA on multiple indices of ALI in wild-type (WT) and gVPLA2-deficient (KO) mice. In vitro, HK-MRSA increased gVPLA2 expression and permeability in human lung EC. Inhibition of gVPLA2 with either the PLA2 inhibitor, LY311727, or with a specific monoclonal antibody, attenuated the barrier disruption caused by HK-MRSA. LY311727 also reduced HK-MRSA-induced permeability in mouse lung EC isolated from WT but not gVPLA2-KO mice. In vivo, live MRSA caused significantly less ALI in gVPLA2 KO mice compared to WT, findings confirmed by intravital microscopy assessment in HK-MRSA-treated mice. After targeted delivery of gVPLA2 plasmid to lung endothelium using ACE antibody-conjugated liposomes, MRSA-induced ALI was significantly increased in gVPLA2-KO mice, indicating that lung endothelial expression of gVPLA2 is critical in vivo. In summary, these results demonstrate an important role for gVPLA2 in mediating MRSA-induced lung EC permeability and ALI. Thus, gVPLA2 may represent a novel therapeutic target in ALI/ARDS caused by bacterial infection.
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Chiba, Takuto, Débora M. Cerqueira, Yao Li, Andrew J. Bodnar, Elina Mukherjee, Katherine Pfister, Yu Leng Phua, et al. "Endothelial-Derived miR-17∼92 Promotes Angiogenesis to Protect against Renal Ischemia-Reperfusion Injury." Journal of the American Society of Nephrology 32, no. 3 (January 29, 2021): 553–62. http://dx.doi.org/10.1681/asn.2020050717.
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BackgroundDamage to the renal microvasculature is a hallmark of renal ischemia-reperfusion injury (IRI)–mediated AKI. The miR-17∼92 miRNA cluster (encoding miR-17, -18a, -19a, -20a, -19b-1, and -92a-1) regulates angiogenesis in multiple settings, but no definitive role in renal endothelium during AKI pathogenesis has been established.MethodsAntibodies bound to magnetic beads were utilized to selectively enrich for renal endothelial cells from mice. Endothelial-specific miR-17∼92 knockout (miR-17∼92endo−/−) mice were generated and given renal IRI. Mice were monitored for the development of AKI using serum chemistries and histology and for renal blood flow using magnetic resonance imaging (MRI) and laser Doppler imaging. Mice were treated with miRNA mimics during renal IRI, and therapeutic efficacies were evaluated.ResultsmiR-17, -18a, -20a, -19b, and pri–miR-17∼92 are dynamically regulated in renal endothelial cells after renal IRI. miR-17∼92endo−/− exacerbates renal IRI in male and female mice. Specifically, miR-17∼92endo−/− promotes renal tubular injury, reduces renal blood flow, promotes microvascular rarefaction, increases renal oxidative stress, and promotes macrophage infiltration to injured kidneys. The potent antiangiogenic factor thrombospondin 1 (TSP1) is highly expressed in renal endothelium in miR-17∼92endo−/− after renal IRI and is a target of miR-18a and miR-19a/b. miR-17∼92 is critical in the angiogenic response after renal IRI, which treatment with miR-18a and miR-19b mimics can mitigate.ConclusionsThese data suggest that endothelial-derived miR-17∼92 stimulates a reparative response in damaged renal vasculature during renal IRI by regulating angiogenic pathways.
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Christofidou-Solomidou, Melpo, Arnaud Scherpereel, Rainer Wiewrodt, Kimmie Ng, Thomas Sweitzer, Evguenia Arguiri, Vladimir Shuvaev, Charalambos C. Solomides, Steven M. Albelda, and Vladimir R. Muzykantov. "PECAM-directed delivery of catalase to endothelium protects against pulmonary vascular oxidative stress." American Journal of Physiology-Lung Cellular and Molecular Physiology 285, no. 2 (August 2003): L283—L292. http://dx.doi.org/10.1152/ajplung.00021.2003.
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Targeted delivery of drugs to vascular endothelium promises more effective and specific therapies in many disease conditions, including acute lung injury (ALI). This study evaluates the therapeutic effect of drug targeting to PECAM (platelet/endothelial cell adhesion molecule-1) in vivo in the context of pulmonary oxidative stress. Endothelial injury by reactive oxygen species (e.g., H2O2) is involved in many disease conditions, including ALI/acute respiratory distress syndrome and ischemia-reperfusion. To optimize delivery of antioxidant therapeutics, we conjugated catalase with PECAM antibodies and tested properties of anti-PECAM/catalase conjugates in cell culture and mice. Anti-PECAM/catalase, but not an IgG/catalase counterpart, bound specifically to PECAM-expressing cells, augmented their H2O2-degrading capacity, and protected them against H2O2 toxicity. Anti-PECAM/catalase, but not IgG/catalase, rapidly accumulated in the lungs after intravenous injection in mice, where it was confined to the pulmonary endothelium. To test its protective effect, we employed a murine model of oxidative lung injury induced by glucose oxidase coupled with thrombomodulin antibody (anti-TM/GOX). After intravenous injection in mice, anti-TM/GOX binds to pulmonary endothelium and produces H2O2, which causes lung injury and 100% lethality within 7 h. Coinjection of anti-PECAM/catalase protected against anti-TM/GOX-induced pulmonary oxidative stress, injury, and lethality, whereas polyethylene glycol catalase or IgG/catalase conjugates afforded only marginal protective effects. This result validates vascular immunotargeting as a prospective strategy for therapeutic interventions aimed at immediate protective effects, e.g., for augmentation of antioxidant defense in the pulmonary endothelium and treatment of ALI.
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Maakaron, Joseph, Emily Stene, Megan Bruns, Todd E. DeFor, Najla H. El Jurdi, Veronika Bachanova, Daniel J. Weisdorf, Jeffrey S. Miller, Murali Janakiram, and Mark Juckett. "Icans Prophylaxis with Simvastatin and Intrathecal Dexamethasone in Adults Receiving Axicabtagene Ciloleucel (Axi-Cel) Treatment." Blood 138, Supplement 1 (November 5, 2021): 1744. http://dx.doi.org/10.1182/blood-2021-149607.
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Abstract Background Axi-cel is approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma since 2017 and has demonstrated efficacy and durability but with significant side effects, namely cytokine release syndrome (CRS) and neurotoxicity (ICANS). In patients receiving axi-cel for aggressive lymphomas, any grade ICANS occurs at a rate of 50% and grade 3/4 occurs about 35% of the time. The mechanism underlying ICANS remains unclear. The current working hypothesis is that endothelial injury caused by the disease and lymphodepleting chemotherapy leads to breakdown of the blood-brain-barrier. Following activation of axi-cel, cytokines are trafficked into the central nervous system leading to local production of cytokines and the clinical syndrome observed. ICANS is treated with systemic steroids with good CNS penetration. Statins have been shown to stabilize the endothelium and have anti-inflammatory effects. We are currently evaluating the safety and feasibility of administering simvastatin to stabilize the endothelium in addition to dexamethasone delivered intrathecally to prevent the occurrence and decrease the severity of neurotoxicity. Methods: This is a feasibility study combining simvastatin 40 mg orally, daily, starting at least 5 days prior to apheresis in addition to dexamethasone delivered intrathecally on days -1, +6, +13 in relation to axi-cel. A schema of the trial is presented in figure 1. This is registered on Clinicaltrials.gov number (NCT04514029). Results: We have accrued 6/20 planned patients with r/r DLBCL who received axi-cel per institutional guidelines. One passed away prior to apheresis due to disease progression and was non-evaluable. Table 1 shows the patient characteristics. With a median follow up of 123 days (50-245), all patients achieved a complete response and remained alive. Table 2 summarizes the feasibility, safety, and dose-density received out of prescribed. None of the 5 patients had grade 3 or 4 ICANS and only 1 patient had grade 1 neurotoxicity (Table 3). A cytokine analysis and markers of endothelial and neuronal activation is underway. Discussion: In a preliminary analysis, simvastatin and intrathecal dexamethasone appears to be feasible to administer, safe and efficacious in a population of patients receiving axi-cel for relapsed and refractory DLBCL. There appears to be a signal in abrogating neurotoxicity without any effect on the efficacy of axi-cel. This will allow for a safer delivery of axi-cel and improve access to this treatment. This study is ongoing. Figure 1 Figure 1. Disclosures Bachanova: FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Miller: Wugen: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Vycellix: Consultancy; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding. Janakiram: FATE, Nektar Therapeutics: Research Funding; Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria. OffLabel Disclosure: Simvastatin is an HMG-CoA reductase inhibitor approved for hyperlipidemia and cardiovascular health.
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Rajendran, Ganeshkumar, Michael P. Schonfeld, Ratnakar Tiwari, Shengping Huang, Rafael Torosyan, Timothy Fields, Jihwan Park, Katalin Susztak, and Pinelopi P. Kapitsinou. "Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1." Journal of the American Society of Nephrology 31, no. 3 (January 29, 2020): 501–16. http://dx.doi.org/10.1681/asn.2019050523.
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BackgroundProlyl-4-hydroxylase domain-containing proteins 1–3 (PHD1 to PHD3) regulate the activity of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2, transcription factors that are key regulators of hypoxic vascular responses. We previously reported that deficiency of endothelial HIF-2 exacerbated renal ischemia-reperfusion injury, whereas inactivation of endothelial PHD2, the main oxygen sensor, provided renoprotection. Nevertheless, the molecular mechanisms by which endothelial PHD2 dictates AKI outcomes remain undefined.MethodsTo investigate the function of the endothelial PHD2/HIF axis in ischemic AKI, we examined the effects of endothelial-specific ablation of PHD2 in a mouse model of renal ischemia-reperfusion injury. We also interrogated the contribution of each HIF isoform by concurrent endothelial deletion of both PHD2 and HIF-1 or both PHD2 and HIF-2.ResultsEndothelial deletion of Phd2 preserved kidney function and limited transition to CKD. Mechanistically, we found that endothelial Phd2 ablation protected against renal ischemia-reperfusion injury by suppressing the expression of proinflammatory genes and recruitment of inflammatory cells in a manner that was dependent on HIF-1 but not HIF-2. Persistence of renoprotective responses after acute inducible endothelial-specific loss of Phd2 in adult mice ruled out a requirement for PHD2 signaling in hematopoietic cells. Although Phd2 inhibition was not sufficient to induce detectable HIF activity in the kidney endothelium, in vitro experiments implicated a humoral factor in the anti-inflammatory effects generated by endothelial PHD2/HIF-1 signaling.ConclusionsOur findings suggest that activation of endothelial HIF-1 signaling through PHD2 inhibition may offer a novel therapeutic approach against ischemic AKI.
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Yin, Xiuru, Zuodi Liang, Yue Yun, and Ling Pei. "Intravenous Transplantation of BMP2-Transduced Endothelial Progenitor Cells Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Rats." Cellular Physiology and Biochemistry 35, no. 6 (2015): 2149–58. http://dx.doi.org/10.1159/000374020.
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Background/Aims: Acute lung injury (ALI) and its aggressive stage, acute respiratory distress syndrome (ARDS), are characterized by diffuse damage and increased permeability of the endothelial barrier, leading to alveolar infiltrates and interstitial edema. Enhancing endothelial integrity represents a novel therapeutic strategy for ALI/ARDS. Endothelial progenitor cells (EPCs) have been reported to participate in endothelial repair of ALI and also serve as a tool for gene therapy. Further, bone morphogenetic protein 2 (BMP2) is an essential signaling molecule that regulates the fate of different cell types. The aim of our study is to explore whether bone marrow-derived EPCs transduced with lentiviral-mediated BMP2 gene might benefit lipopolysaccharide (LPS)-induced ALI in a rat model. Methods: Rats were divided randomly into five groups. The sham group was given normal saline via the trachea and right jugular vein. The other four groups underwent intratracheal-LPS-induced ALI followed after 30 min by treatment with either normal saline, EPCs, EPCs transduced with empty lentiviral vector (EPCs-null), or EPCs transduced with BMP2 (EPCs-BMP2) via the right jugular vein. Results: We found that the lung injury score, oxygenation, and inflammatory response were significantly ameliorated in the three EPC-treated groups (EPCs, EPCs-null, and EPCs-BMP2). In addition, EPCs-BMP2 further improved endothelium repair and capillary permeability, causing markedly reduced wet-to-dry lung-weight ratio and BALF protein content, and increased levels of BMP2 protein, BMP2 mRNA, and eNOS protein in lung tissues. Conclusion: Transplantation of BMP2-transduced EPCs effectively attenuates edema and protein exudation compared with EPCs alone in LPS-induced ALI via enhanced expression of BMP2 and eNOS.
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Marrazzo, Francesco, Stefano Spina, Francesco Zadek, Tenzing Lama, Changhan Xu, Grant Larson, Emanuele Rezoagli, et al. "Protocol of a randomised controlled trial in cardiac surgical patients with endothelial dysfunction aimed to prevent postoperative acute kidney injury by administering nitric oxide gas." BMJ Open 9, no. 7 (July 2019): e026848. http://dx.doi.org/10.1136/bmjopen-2018-026848.
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IntroductionPostoperative acute kidney injury (AKI) is a common complication in cardiac surgery. Levels of intravascular haemolysis are strongly associated with postoperative AKI and with prolonged (>90 min) use of cardiopulmonary bypass (CPB). Ferrous plasma haemoglobin released into the circulation acts as a scavenger of nitric oxide (NO) produced by endothelial cells. Consequently, the vascular bioavailability of NO is reduced, leading to vasoconstriction and impaired renal function. In patients with cardiovascular risk factors, the endothelium is dysfunctional and cannot replenish the NO deficit. A previous clinical study in young cardiac surgical patients with rheumatic fever, without evidence of endothelial dysfunction, showed that supplementation of NO gas decreases AKI by converting ferrous plasma haemoglobin to ferric methaemoglobin, thus preserving vascular NO. In this current trial, we hypothesised that 24 hours administration of NO gas will reduce AKI following CPB in patients with endothelial dysfunction.MethodsThis is a single-centre, randomised (1:1) controlled, parallel-arm superiority trial that includes patients with endothelial dysfunction, stable kidney function and who are undergoing cardiac surgery procedures with an expected CPB duration >90 min. After randomisation, 80 parts per million (ppm) NO (intervention group) or 80 ppm nitrogen (N2, control group) are added to the gas mixture. Test gases (N2or NO) are delivered during CPB and for 24 hours after surgery. The primary study outcome is the occurrence of AKI among study groups. Key secondary outcomes include AKI severity, occurrence of renal replacement therapy, major adverse kidney events at 6 weeks after surgery and mortality. We are recruiting 250 patients, allowing detection of a 35% AKI relative risk reduction, assuming a two-sided error of 0.05.Ethics and disseminationThe Partners Human Research Committee approved this trial. Recruitment began in February 2017. Dissemination plans include presentations at scientific conferences, scientific publications and advertising flyers and posters at Massachusetts General Hospital.Trial registration numberNCT02836899.
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Agneskirchner, Jens, Patrick Bode, Michael Spannagl, Laurenz Wurzinger, and Armin Reininger. "c7E3 Fab Inhibits Low Shear Flow Modulated Platelet Adhesion to Endothelium and Surface-adsorbed Fibrinogen by Blocking Platelet GP IIb/IIIa as well as Endothelial Vitronectin Receptor." Thrombosis and Haemostasis 83, no. 02 (2000): 217–23. http://dx.doi.org/10.1055/s-0037-1613789.
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SummaryThe c7E3 Fab reduces ischemic complications in patients undergoing high-risk coronary angioplasty or atherectomy. The present study investigated how c7E3 Fab inhibition of the platelet receptor glycoprotein IIb/IIIa and the endothelial vitronectin receptor affected platelet adhesion to endothelium and surface adsorbed fibrinogen under flow conditions.Platelet adhesion was examined using a stagnation point flow device with shear stress and shear rates up to 2.2 dynes/cm2 and 170 s−1, respectively. Ex vivo adhesion was compared between two groups of patients with acute myocardial infarction (AMI) treated with angioplasty and stent implantation and a group of healthy controls. Only one AMI group received c7E3 Fab therapy. Patients in both groups were administered acetyl salicylic acid (ASA) and heparin. In AMI patients c7E3 Fab reduced platelet adhesion to adsorbed fibrinogen by 79% compared to AMI patients without c7E3 Fab treatment and by 74% compared to healthy controls. Thirty hours after termination of c7E3 Fab infusion adhesion had slightly recovered with an inhibition of 61% and 52% still present, respectively. Additionally, in vitro platelet adhesion to intact endothelium and to adsorbed fibrinogen was measured during superfusion with ADP stimulated platelet rich plasma of healthy controls to which c7E3 Fab was added at a final concentration fc of 20 µg/ml. In spite of ADP stimulation c7E3 Fab completely blocked platelet adhesion to adsorbed fibrinogen and, moreover, to intact endothelium. Preincubation of endothelial cells with c7E3 (fc = 20 µg/ml) blocked adhesion of ADP-stimulated platelets by approximately 50%.Apart from the inhibition of platelet aggregation, c7E3 Fab added in vitro and given therapeutically in patients effectively blocks platelet adhesion to components of the injured as well as intact vessel wall under stagnation point flow conditions.
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Agarwal, Neera, Sam P. L. Rice, Hemanth Bolusani, Stephen D. Luzio, Gareth Dunseath, Marian Ludgate, and D. Aled Rees. "Metformin Reduces Arterial Stiffness and Improves Endothelial Function in Young Women with Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled, Crossover Trial." Journal of Clinical Endocrinology & Metabolism 95, no. 2 (February 1, 2010): 722–30. http://dx.doi.org/10.1210/jc.2009-1985.
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Abstract Context: Patients with polycystic ovary syndrome (PCOS) have an increased prevalence of insulin resistance and display subclinical evidence of early cardiovascular disease. Metformin improves insulin sensitivity and circulating markers of cardiovascular risk in patients with PCOS, but it is unclear whether this translates into improvements in vascular function. Objective: Our objective was to evaluate the effects of metformin on arterial stiffness and endothelial function in women with PCOS. Design and Intervention: Thirty women with PCOS were assigned to consecutive 12-wk treatment periods of metformin or placebo in a randomized, double-blind, crossover design separated by an 8-wk washout. Main Outcome Measures: The primary outcome measures were assessments of arterial stiffness [augmentation index (AIx), central blood pressure, and brachial and aortic pulse wave velocity (PWV)] and endothelial function. Anthropometry, testosterone, and metabolic biochemistry (lipids, homeostasis model of assessment for insulin resistance, high-sensitivity C-reactive protein, adiponectin, and plasminogen activator inhibitor-1) were also assessed. Results: Metformin improved AIx [−6.1%; 95% confidence interval (CI) for the difference −8.5 to −3.5%; P < 0.001], aortic PWV (−0.76 m/sec; 95% CI for the difference −1.12 to −0.4 m/sec; P < 0.001), brachial PWV (−0.73 m/sec; 95% CI for the difference −1.09 to −0.38; P < 0.001), central blood pressure (P < 0.001), and endothelium-dependent (AIx after albuterol; P = 0.003) and endothelium-independent (AIx after nitroglycerin; P < 0.001) vascular responses. Metformin also reduced weight (P < 0.001), waist circumference (P < 0.001), and triglycerides (P = 0.004) and increased adiponectin (P = 0.001) but did not affect testosterone or other metabolic measures. Conclusions: Short-term metformin therapy improves arterial stiffness and endothelial function in young women with PCOS.
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Hartopo, Anggoro Budi, and Lucia Kris Dinarti. "The Shared Pathogenesis of Pulmonary Artery Hypertension." ACI (Acta Cardiologia Indonesiana) 4, no. 1 (July 6, 2018): 22. http://dx.doi.org/10.22146/aci.36635.
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Pulmonary artery hypertension is defined as an increased in pulmonary artery pressureexceeding 25 mmHg with normal pulmonary wedge pressure. The pathogenesis of pulmonaryartery hypertension involves interaction among vascular, cellular and biomarker componentsin the pulmonary tissue; with eventual result is elevated pulmonary artery pressure. Vascularcomponents are remodeling of intimal, medial and adventitial layers. Cellular components areplayed by apoptosis-resistant endothelial cells, proliferative-prone pulmonary artery smoothmuscle cells, fibroblasts and inflammatory cells. The functional biomarkers are produced andmediated by these cellular changes, mainly endothelin-1, thromboxane, serotonin, nitric oxide,and prostacyclin. The pulmonary vascular remodeling in pulmonary artery hypertension arediverse and may present in various severity based on underlying etiology. Understanding theshared pathogenesis in pulmonary artery hypertension is of paramount importance in order toimprove the disease management and treatment approach.
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Hanke, Craig J., Blythe B. Holmes, Yafei Xu, Kasem Nithipatikom, and William B. Campbell. "Endothelium-Derived Steroidogenic Factor Enhances Angiotensin II-Stimulated Aldosterone Release by Bovine Zona Glomerulosa Cells." Endocrinology 148, no. 1 (January 1, 2007): 317–23. http://dx.doi.org/10.1210/en.2006-0884.
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Endothelium-derived steroidogenic factor (EDSF) is an endothelial peptide that stimulates aldosterone release from bovine adrenal zona glomerulosa (ZG) cells. The regulation of aldosterone release by combinations of EDSF and angiotensin II (AII) or EDSF and ACTH was investigated. Endothelial cells (ECs) and EC-conditioned media (ECCM) increased aldosterone release from ZG cells, an activity attributed to EDSF. AII (10−12 to 10−8m) and ACTH (10−12 to 10−9m) also stimulated the release of aldosterone from ZG cells. The stimulation by AII, but not ACTH, was greatly enhanced when ZG cells were coincubated with ECs. AII was metabolized by ECs to peptides identified by mass spectrometry as angiotensin (1-7) and angiotensin IV. There was very little metabolism of AII by ZG cells. Neither of these two AII metabolites altered aldosterone release from ZG cells, so they could not account for the enhanced response with ECs. AII-induced aldosterone release from ZG cells was enhanced by ECCM but not cell-free conditioned medium. This enhanced response was not due to increased EDSF release from ECs by AII. The synergistic effect of EDSF and AII was apparent when AII was added during or after the generation of ECCM and not observed when the AII component of the enhancement was blocked by the AII antagonist, losartan. These studies indicate that EDSF enhances the steroidogenic effect of AII. In the adrenal gland, ECs are in close anatomical relationship with ZG cells and may sensitize ZG cells to the steroidogenic action of AII by releasing EDSF.
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Tuychiev, L. N., M. D. Ahkmedova, I. A. Imamova, N. U. Ibragimova, and S. D. Igamberdieva. "Predisposing factors contributing to the development of renal dysfunction in acute infectious diarrhea associated with hemocolitis (AIDH)." Journal Infectology 12, no. 5 (January 21, 2021): 123–29. http://dx.doi.org/10.22625/2072-6732-2020-12-5-123-129.
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Outcomes of severe variants of acute infectious diarrhea in children with acute renal injury/failure (ARI/ARF) remain unsatisfactory, and mortality reaches 70% and more. ARI/ ARF therapy requires high material costs, which represent significant burden on health financing systems. It makes us consider AFR as one of the most important medical and social problems.The aim of our study was to investigate predisposing factors contributing to the development of renal dysfunction in acute infectious diarrhea associated with hemocolitis (AIDH), as well as to study the relationship of the developed renal dysfunction with the severity of endogenous intoxication, damage of vascular endothelium and hemostasis system.We examined 60 sick children with AIDH, divided into two groups: with ARF and without kidney pathology.Susceptibility to ARI/ARF in severe forms of AIDH is mediated by early childhood (up to 3 years in 89,5% of patients), artificial and mixed feeding (in 52,6% and 36,8% of children respectively), pathology of pregnancy in the first trimester, mother diseases during pregnancy (84,2%) and the late admission to hospital (89,5%) on the 4,9±0,2 day of the disease, i/m administration of furosemide without volume circulating blood restoration, i/m administration of nephrotoxic antibacterial medicines. Shigella spp. and Escherichia coli as etiologic factors of diarrhea in 42,1% and 47,4% of cases respectively. Thus due these parameters we can predict the loss of kidneys adaptation ability in diseases with severe course including acute infectious diarrheas.Interrelationships between elevation of the number of antigen binding lymphocytes to tissue antigens of vascular endothelium up to 8,1±0,6% in children with ARF and development of hemorrhagic syndrome (decrease of PTI to 72,5%) and intensity of endogenic intoxication (average molecular peptides up to 9,7±0,6 g/l) and worsening of AFR signs were established.Thus, it was found that AKI most often develops when rehydration therapy is started late or inferiorly performed, when nephrotoxic antibiotics and loop diuretics are prescribed without circulating blood volume (CBV) compensation and is accompanied by an increase in the degree of endogenous intoxication and vascular endothelial damage.
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Mutin, Murielle, Isabelle Canavy, Andrew Blann, Michel Bory, José Sampol, and Françoise Dignat-George. "Direct Evidence of Endothelial Injury in Acute Myocardial Infarction and Unstable Angina by Demonstration of Circulating Endothelial Cells." Blood 93, no. 9 (May 1, 1999): 2951–58. http://dx.doi.org/10.1182/blood.v93.9.2951.
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Abstract Circulating endothelial cells (CECs) have been detected in association with endothelial injury and therefore represent proof of serious damage to the vascular tree. Our aim was to investigate, using the technique of immunomagnetic separation, whether the pathological events in unstable angina (UA) or acute myocardial infarction (AMI) could cause desquamation of endothelial cells in circulating blood compared with effort angina (EA) and noncoronary chest pain. A high CEC count was found in AMI (median, 7.5 cells/mL; interquartile range, 4.1 to 43.5, P < .01 analysis of variance [ANOVA]) and UA (4.5; 0.75 to 13.25 cells/mL, P < .01) within 12 hours after chest pain as compared with controls (0; 0 to 0 cells/mL) and stable angina (0; 0 to 0 cells/mL). CEC levels in serial samples peaked at 15.5 (2.7 to 39) cells/mL 18 to 24 hours after AMI (P < .05 repeated measures ANOVA), but fell steadily after UA. Regardless of acute coronary events, the isolated cells displayed morphologic and immunologic features of vascular endothelium. The CECs were predominantly of macrovascular origin. They did not express the activation markers intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin, although some were positive for tissue factor. CECs failed to exhibit characteristics of apoptosis (TUNEL assay) excluding this event as a possible mechanism of cell detachment. The presence of CECs provides direct evidence of endothelial injury in AMI and UA, but not in stable angina, confirming that these diseases have different etiopathogenic mechanisms.
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Mutin, Murielle, Isabelle Canavy, Andrew Blann, Michel Bory, José Sampol, and Françoise Dignat-George. "Direct Evidence of Endothelial Injury in Acute Myocardial Infarction and Unstable Angina by Demonstration of Circulating Endothelial Cells." Blood 93, no. 9 (May 1, 1999): 2951–58. http://dx.doi.org/10.1182/blood.v93.9.2951.409k02_2951_2958.
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Circulating endothelial cells (CECs) have been detected in association with endothelial injury and therefore represent proof of serious damage to the vascular tree. Our aim was to investigate, using the technique of immunomagnetic separation, whether the pathological events in unstable angina (UA) or acute myocardial infarction (AMI) could cause desquamation of endothelial cells in circulating blood compared with effort angina (EA) and noncoronary chest pain. A high CEC count was found in AMI (median, 7.5 cells/mL; interquartile range, 4.1 to 43.5, P < .01 analysis of variance [ANOVA]) and UA (4.5; 0.75 to 13.25 cells/mL, P < .01) within 12 hours after chest pain as compared with controls (0; 0 to 0 cells/mL) and stable angina (0; 0 to 0 cells/mL). CEC levels in serial samples peaked at 15.5 (2.7 to 39) cells/mL 18 to 24 hours after AMI (P < .05 repeated measures ANOVA), but fell steadily after UA. Regardless of acute coronary events, the isolated cells displayed morphologic and immunologic features of vascular endothelium. The CECs were predominantly of macrovascular origin. They did not express the activation markers intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin, although some were positive for tissue factor. CECs failed to exhibit characteristics of apoptosis (TUNEL assay) excluding this event as a possible mechanism of cell detachment. The presence of CECs provides direct evidence of endothelial injury in AMI and UA, but not in stable angina, confirming that these diseases have different etiopathogenic mechanisms.
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Millar, Michelle Warren, Fabeha Fazal, and Arshad Rahman. "Therapeutic Targeting of NF-κB in Acute Lung Injury: A Double-Edged Sword." Cells 11, no. 20 (October 21, 2022): 3317. http://dx.doi.org/10.3390/cells11203317.
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Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a devastating disease that can be caused by a variety of conditions including pneumonia, sepsis, trauma, and most recently, COVID-19. Although our understanding of the mechanisms of ALI/ARDS pathogenesis and resolution has considerably increased in recent years, the mortality rate remains unacceptably high (~40%), primarily due to the lack of effective therapies for ALI/ARDS. Dysregulated inflammation, as characterized by massive infiltration of polymorphonuclear leukocytes (PMNs) into the airspace and the associated damage of the capillary-alveolar barrier leading to pulmonary edema and hypoxemia, is a major hallmark of ALI/ARDS. Endothelial cells (ECs), the inner lining of blood vessels, are important cellular orchestrators of PMN infiltration in the lung. Nuclear factor-kappa B (NF-κB) plays an essential role in rendering the endothelium permissive for PMN adhesion and transmigration to reach the inflammatory site. Thus, targeting NF-κB in the endothelium provides an attractive approach to mitigate PMN-mediated vascular injury, not only in ALI/ARDS, but in other inflammatory diseases as well in which EC dysfunction is a major pathogenic mechanism. This review discusses the role and regulation of NF-κB in the context of EC inflammation and evaluates the potential and problems of targeting it as a therapy for ALI/ARDS.
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Su, Vincent Yi-Fong, Shih-Hwa Chiou, Wei-Chih Chen, Wen-Kuang Yu, Huai-Hsuan Wu, Hao Chen, and Kuang-Yao Yang. "Induced Pluripotent Stem Cell-Derived Conditioned Medium Promotes Endogenous Leukemia Inhibitory Factor to Attenuate Endotoxin-Induced Acute Lung Injury." International Journal of Molecular Sciences 22, no. 11 (May 24, 2021): 5554. http://dx.doi.org/10.3390/ijms22115554.
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The conditioned medium of induced pluripotent stem cells (iPSC-CM) can attenuate neutrophil recruitment and endothelial leakage of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Therefore, we investigated the mechanisms by which iPSC-CM regulate the interaction between neutrophils and the endothelium in ALI. Murine iPSCs (miPSCs) were delivered intravenously to male C57BL/6 mice (8–12 weeks old) 4 h after intratracheal LPS injection. A miPSC-derived conditioned medium (miPSC-CM) was delivered intravenously to mice after intratracheal LPS injection. DMSO-induced HL-60 cells (D-HL-60, neutrophil-like cells) and human umbilical vein endothelial cells (HUVECs) were used as in vitro models to assess the interaction of neutrophils and endothelial cells. miPSC-CM diminished the histopathological changes in the lungs and the neutrophil count in bronchoalveolar lavage fluids of ALI mice. miPSC-CM attenuated the expression of adhesion molecules in the lungs of ALI mice. Human iPSC conditioned medium (hiPSC-CM) reduced the expression of adhesion molecules in a HUVEC and D-HL-60 co-culture after LPS stimulation, which decreased the transendothelial migration (TEM) of D-HL-60. A human angiogenesis factors protein array revealed that leukemia inhibitory factor (LIF) was not detected in the absence of D-HL-60 and hiPSC-CM groups. hiPSC-CM significantly promoted the production of endogenous LIF in in vitro models. Administration of an anti-LIF antibody not only reversed the effect of iPSC-CM in ALI mice, but also blocked the effect of iPSC-CM on neutrophils TEM in in vitro models. However, a controlled IgG had no such effect. Our study demonstrated that iPSC-CM promoted endogenous LIF to inhibit neutrophils TEM and attenuate the severity of sepsis-induced ALI.
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MOREY, K. Anjali, Mahnaz RAZANDI, Ali PEDRAM, Ren-Ming HU, A. Bruce PRINS, and R. Ellis LEVIN. "Oestrogen and progesterone inhibit the stimulated production of endothelin-1." Biochemical Journal 330, no. 3 (March 15, 1998): 1097–105. http://dx.doi.org/10.1042/bj3301097.
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Important vascular proteins such as endothelin-1 (ET-1) promote the development of cardiovascular diseases. Oestrogen, and perhaps progesterone, prevent the development of vascular disease in women through incompletely understood cellular mechanisms. We hypothesized that oestradiol or progesterone might regulate the production of ET-1 as a potential novel mechanism. We found that serum and angiotensin II (AII) significantly stimulated ET-1 secretion from cultured bovine aortic endothelial cells, inhibited 50-75% by oestradiol or by progesterone. Serum and AII stimulated ET-1 mRNA levels, inhibited at least 70% by oestradiol and by progesterone. Serum stimulated ET-1 transcription mainly through the first 43 nucleotides of the ET-1 promoter, but oestradiol and progesterone did not inhibit this. In contrast, AII stimulated ET-1 transcription through nucleotides -143 to -98, specifically involving an activator protein-1 (AP-1) site at -102. Oestradiol and progesterone caused a 60-70% inhibition of AII-stimulated wild-type construct -.143ET-1/CAT activity (CAT is chloramphenicol acyltransferase). AII-stimulation of ET-1 transcription was critically dependent on stimulation of mitogen-activated protein kinase (erk) activity, inhibited by oestradiol and progesterone. In summary, we found that sex steroids inhibit AII-induced erk signalling to the ET-1 transcriptional programme. This novel mechanism of negative transcriptional regulation by oestradiol and progesterone decreases the production of ET-1, potentially contributing to the vascular protective effects of these steroids.
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Hassoun, Heitham T., Mihaela L. Lie, Dmitry N. Grigoryev, Manchang Liu, Rubin M. Tuder, and Hamid Rabb. "Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis." American Journal of Physiology-Renal Physiology 297, no. 1 (July 2009): F125—F137. http://dx.doi.org/10.1152/ajprenal.90666.2008.
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Distant organ effects of acute kidney injury (AKI) are a leading cause of morbidity and mortality. While little is known about the underlying mechanisms, limited data suggest a role for inflammation and apoptosis. Utilizing a lung candidate gene discovery approach in a mouse model of ischemic AKI-induced lung dysfunction, we identified prominent lung activation of 66 apoptosis-related genes at 6 and/or 36 h following ischemia, of which 6 genes represent the tumor necrosis factor receptor (TNFR) superfamily, and another 23 genes are associated with the TNFR pathway. Given that pulmonary apoptosis is an important pathogenic mechanism of acute lung injury (ALI), we hypothesized that AKI leads to pulmonary proapoptotic pathways that facilitate lung injury and inflammation. Functional correlation with 1) terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and 2) active caspase-3 (aC3) activity, immunoblotting, and immunohistochemistry (IHC) identified kidney IRI-induced pulmonary apoptosis at 24 h, and colocalization studies with CD34 identified predominantly endothelial apoptosis. Mice were treated with the caspase inhibitor Z-VAD-FMK (0.25 mg ip) or vehicle 1 h before and 8 h after sham or kidney IRI, and bronchoalveolar lavage fluid protein was measured at 36 h as a surrogate for lung leak. Caspase inhibition reduced lung microvascular changes after kidney IRI. The pulmonary apoptosis seen in wild-type control mice during AKI was absent in TNFR−/− mice. Using an initial genomic approach to discovery followed by a mechanistic approach to disease targeting, we demonstrate that pulmonary endothelial apoptosis is a direct mediator of the distant organ dysfunction during experimental AKI.
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Yin, Yujie, Qian Zhang, Qifei Zhao, Guoyuan Ding, Cong Wei, Liping Chang, Hongrong Li, et al. "Tongxinluo Attenuates Myocardiac Fibrosis after Acute Myocardial Infarction in Rats via Inhibition of Endothelial-to-Mesenchymal Transition." BioMed Research International 2019 (June 16, 2019): 1–13. http://dx.doi.org/10.1155/2019/6595437.
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Endothelial-to-mesenchymal transition (EndMT) is an essential mechanism in myocardial fibrosis (MF). Tongxinluo (TXL) has been confirmed to protect the endothelium against reperfusion injury after acute myocardial infarction (AMI). However, whether TXL can inhibit MF after AMI via inhibiting EndMT remained unknown. This study aims to identify the role of EndMT in MF after AMI as well as the protective effects and underlying mechanisms of TXL on MF. The AMI model was established in rats by ligating left anterior descending coronary artery. Then, rats were administered with high- (0.8 g·kg−1·d−1), mid- (0.4 g·kg−1·d−1), and low- (0.2 g·kg−1·d−1) dose Tongxinluo and benazepril for 4 weeks, respectively. Cardiac function, infarct size, MF, and related indicators of EndMT were measured. In vitro, human cardiac microvascular endothelial cells (HCMECs) were pretreated with TXL for 4 h and then incubated in hypoxia conditions for 3 days to induce EndMT. Under this hypoxic condition, neuregulin-1 (NRG-1) siRNA were further applied to silence NRG-1 expression. Immunofluorescence microscopy was used to assess expression of endothelial marker of vWF and fibrotic marker of Vimentin. Related factors of EndMT were determined by Western blot analysis. TXL treatment significantly improved cardiac function, ameliorated MF, reduced collagen of fibrosis area (types I and III collagen) and limited excessive extracellular matrix deposition (mmp2 and mmp9). In addition, TXL inhibited EndMT in cardiac tissue and hypoxia-induced HCMECs. In hypoxia-induced HCMECs, TXL increased the expression of endothelial markers, whereas decreasing the expression of fibrotic markers, partially through enhanced expressions of NRG-1, phosphorylation of ErbB2, ErbB4, AKT, and downregulated expressions of hypoxia inducible factor-1a and transcription factor snail. After NRG-1 knockdown, the protective effect of TXL on HCMEC was partially abolished. In conclusion, TXL attenuates MF after AMI by inhibiting EndMT and through activating the NRG-1/ErbB- PI3K/AKT signalling cascade.
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Kwon, Osun, Seok-Min Hong, and Ganesan Ramesh. "Diminished NO generation by injured endothelium and loss of macula densa nNOS may contribute to sustained acute kidney injury after ischemia-reperfusion." American Journal of Physiology-Renal Physiology 296, no. 1 (January 2009): F25—F33. http://dx.doi.org/10.1152/ajprenal.90531.2008.
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In postischemic acute kidney injury (AKI) or acute renal failure, a dissipation of glomerular filtration pressure is associated with an altered renal vascular tone and reactivity, as well as a loss of vascular autoregulation. To test the hypothesis that renal nitric oxide (NO) generation reflects endothelial damage in the kidney after ischemia-reperfusion, we quantified the urinary NO levels and identified the site of its generation in postischemic AKI. Subjects were 50 recipients of cadaveric renal allografts: 15 with sustained AKI and 35 with recovering renal function. Urine and blood samples were obtained after transplant, and intraoperative allograft biopsies were performed to examine NO synthases (NOSs) in the kidney. In the sustained AKI group, urinary nitrite and nitrate excretion (in μmol/g urine creatinine) was lower (12.3 ± 1.8 and 10.0 ± 1.4 on postoperative days 0 and 3) than in the recovery group [20.0 ± 3.6 and 35.1 ± 5.3 ( P < 0.005 vs. sustained AKI on days 0 and 3) on postoperative days 0 and 3]. Endothelial NOS expression diminished from the peritubular capillaries of 6 of 7 subjects in the sustained AKI group but from only 6 of 16 subjects in the recovery group. No differences were observed in the inducible NOS staining pattern between the two groups. Neuronal NOS staining was rarely observed in the macula densae of subjects but was prominent in control tissues. These findings suggest that a diminished NO generation by injured endothelium and loss of macula densa neuronal NOS could impair the vasodilatory ability of the renal vasculature and contribute to the reduction in the glomerular filtration rate in postischemic AKI.
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Wu, Xiaoyan, Rongqing Guo, Peili Chen, Quan Wang, and Patrick N. Cunningham. "TNF induces caspase-dependent inflammation in renal endothelial cells through a Rho- and myosin light chain kinase-dependent mechanism." American Journal of Physiology-Renal Physiology 297, no. 2 (August 2009): F316—F326. http://dx.doi.org/10.1152/ajprenal.00089.2009.
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The pathogenesis of LPS-induced acute kidney injury (AKI) requires signaling through tumor necrosis factor-α (TNF) receptor 1 (TNFR1), which within the kidney is primarily located in the endothelium. We showed previously that caspase inhibition protected mice against LPS-induced AKI and in parallel significantly inhibited LPS-induced renal inflammation. Therefore we hypothesized that caspase activation amplifies TNF-induced inflammation in renal endothelial cells (ECs). In cultured renal ECs, TNF induced apoptosis through a caspase-8-dependent pathway. TNF caused translocation of the p65 subunit of NF-κB to the nucleus, resulting in upregulation of inflammatory markers such as adhesion molecules ICAM-1 and VCAM-1. However, the broad-spectrum caspase inhibitor Boc-d-fmk reduced NF-kB activation as assessed by gel shift assay, reduced phosphorylation of subunit IκBα, and significantly inhibited TNF-induced expression of ICAM-1 and VCAM-1 as assessed by both real-time PCR and flow cytometry. Broad-spectrum caspase inhibition markedly inhibited neutrophil adherence to the TNF-activated endothelial monolayer, supporting the functional significance of this effect. Specific inhibitors of caspases-8 and -3, but not of caspase-1, reduced TNF-induced NF-κB activation. Caspase inhibition also reduced TNF-induced myosin light chain (MLC)-2 phosphorylation, and activation of upstream regulator RhoA. Consistent with this, MLC kinase (MLCK) inhibitor ML-7 reduced TNF-induced NF-κB activation. Thus caspase activation influences NF-κB signaling via its affect on cytoskeletal changes occurring through RhoA and MLCK pathways. These cell culture experiments support a role for caspase activation in TNF-induced inflammation in the renal endothelium, a key event in LPS-induced AKI.
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Wu, Yanyan, Rong Huang, Xu Zhong, and Yi Xiao. "Cardiovascular Consequences of Repetitive Arousals over the Entire Sleep Duration." BioMed Research International 2017 (2017): 1–8. http://dx.doi.org/10.1155/2017/4213861.
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Objectives. To explore the cardiovascular effects of nightlong repetitive arousals (RA).Methods. Twenty healthy subjects participated in two consecutive sleep studies. The first one was free of intervention and the second study involved repetitive arousals induced by acoustical stimuli. Blood pressure, heart rate variability (HRV), arterial stiffness index (ASI), and serum markers including nitric oxide (NO), endothelin-1 (ET-1), C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), and vascular endothelial growth factor (VEGF) were studied.Results. RA led to overnight elevation in diastolic blood pressure (DBP) but not in systolic blood pressure (SBP). Regarding HRV, overnight increase in low frequency power (LF) and low frequency to high frequency ratio (LHR) and decrease in high frequency power (HF) were evident. The relative overnight differences in HF and LHR correlated with the amount of rapid-eye movement (REM) sleep. RA did not cause detectable change in either ASI or serum markers of interest.Conclusions. Nightlong RA alters the sympathovagal modulation significantly and this effect seems to be associated with the amount of REM sleep. Exposure to RA also causes an elevation in postsleep DBP. Disturbance to autonomic nervous system (ANS) may precede endothelial dysfunction and increased arterial stiffness as cardiovascular consequences of RA.
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Schunk, Stefan J., Sarah Triem, David Schmit, Stephen Zewinger, Tamim Sarakpi, Ellen Becker, Gregor Hütter, et al. "Interleukin-1α Is a Central Regulator of Leukocyte-Endothelial Adhesion in Myocardial Infarction and in Chronic Kidney Disease." Circulation 144, no. 11 (September 14, 2021): 893–908. http://dx.doi.org/10.1161/circulationaha.121.053547.
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Background: Cardiovascular diseases and chronic kidney disease (CKD) are highly prevalent, aggravate each other, and account for substantial mortality. Both conditions are characterized by activation of the innate immune system. The alarmin interleukin-1α (IL-1α) is expressed in a variety of cell types promoting (sterile) systemic inflammation. The aim of the present study was to examine the role of IL-1α in mediating inflammation in the setting of acute myocardial infarction (AMI) and CKD. Methods: We assessed the expression of IL-1α on the surface of monocytes from patients with AMI and patients with CKD and determined its association with atherosclerotic cardiovascular disease events during follow-up in an explorative clinical study. Furthermore, we assessed the inflammatory effects of IL-1α in several organ injury models in Il1a −/ − and Il1b −/ − mice and investigated the underlying mechanisms in vitro in monocytes and endothelial cells. Results: IL-1α is strongly expressed on the surface of monocytes from patients with AMI and CKD compared with healthy controls. Higher IL-1α surface expression on monocytes from patients with AMI and CKD was associated with a higher risk for atherosclerotic cardiovascular disease events, which underlines the clinical relevance of IL-1α. In mice, IL-1α, but not IL-1β, mediates leukocyte-endothelial adhesion as determined by intravital microscopy. IL-1α promotes accumulation of macrophages and neutrophils in inflamed tissue in vivo. Furthermore, IL-1α on monocytes stimulates their homing at sites of vascular injury. A variety of stimuli such as free fatty acids or oxalate crystals induce IL-1α surface expression and release by monocytes, which then mediates their adhesion to the endothelium via IL-1 receptor-1. IL-1α also promotes expression of the VCAM-1 (vascular cell adhesion molecule-1) on endothelial cells, thereby fostering the adhesion of circulating leukocytes. IL-1α induces inflammatory injury after experimental AMI, and abrogation of IL-1α prevents the development of CKD in oxalate or adenine-fed mice. Conclusions: IL-1α represents a key mediator of leukocyte-endothelial adhesion and inflammation in AMI and CKD. Inhibition of IL-1α may serve as a novel anti-inflammatory treatment strategy.
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NYSTRÖM, Thomas, Arne NYGREN, and Åke SJÖHOLM. "Persistent endothelial dysfunction is related to elevated C-reactive protein (CRP) levels in Type II diabetic patients after acute myocardial infarction." Clinical Science 108, no. 2 (January 21, 2005): 121–28. http://dx.doi.org/10.1042/cs20040243.
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The atherosclerotic process is an ongoing dynamic and progressive state arising from endothelial dysfunction and inflammation. Although suffering from an acute coronary artery disease, patients with Type II diabetes have a poor outcome compared with non-diabetic patients, which may only partly be explained by traditional risk factors. Our purpose was to compare non-traditional risk factors, such as endothelial function, C-reactive protein (CRP) and adiponectin, in Type II diabetic and non-diabetic patients following AMI (acute myocardial infarction). Twenty Type II diabetic patients were compared with 25 non-diabetic patients at baseline (1–3 days from the onset of chest pain) and at 60 days follow-up after an AMI. Using high-resolution ultrasound, brachial artery responses to FMD (flow-mediated vasodilatation; endothelium-dependent vasodilatation) and NTG (nitroglycerine-induced vasodilatation; endothelium-independent vasodilatation) were measured. Plasma levels of CRP and adiponectin were measured by ELISA. At baseline, FMD (1.9 compared with 3.2%; P=0.22) and CRP levels (6.95 compared with. 5.51 mg/l; P=0.40) did not differ between Type II diabetic and non-diabetic patients, whereas adiponectin levels were lower in Type II diabetic patients (2.8 compared with 5.0 ng/ml; P<0.05). At 60 days follow-up, there were significant differences in FMD (1.5 compared with 4.1%; P<0.02), CRP (4.23 compared with 1.46 mg/ml; P<0.01) and adiponectin (3.3 compared with 5.3 ng/ml; P<0.05) levels between Type II diabetic and non-diabetic patients. In contrast, NTG responses improved in both groups between baseline and follow-up (Type II diabetic patients, 9.7 compared with 13.2% respectively, P<0.05; non-diabetic patients, 7.9 compared with 12.4% respectively, P<0.01). These results show a persistent endothelium-dependent dysfunction and inflammatory activity in patients with Type II diabetes, but not in non-diabetic patients, after AMI. These findings may, in part explain, the poor outcome in coronary artery disease seen in Type II diabetes.
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Yin, Jie, Hong Chang, Dongmei Wang, Haifei Li, and Aibing Yin. "Fuzzy C-Means Clustering Algorithm-Based Magnetic Resonance Imaging Image Segmentation for Analyzing the Effect of Edaravone on the Vascular Endothelial Function in Patients with Acute Cerebral Infarction." Contrast Media & Molecular Imaging 2021 (July 14, 2021): 1–8. http://dx.doi.org/10.1155/2021/4080305.
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This paper aimed to discuss the denoising ability of magnetic resonance imaging (MRI) images based on fuzzy C-means clustering (FCM) algorithm and the influence of Butylphthalide combined with Edaravone treatment on nerve function and vascular endothelial function in patients with acute cerebral infarction (ACI). Based on FCM algorithm, Markov Random Field (MRF) model algorithm was introduced to obtain a novel algorithm (NFCM), which was compared with FCM and MRF algorithm in terms of misclassification rate (MCR) and difference of Kappa index (KI). 90 patients with ACI diagnosed in hospital from December 2018 to December 2019 were selected as subjects, who were divided into combined treatment group (conventional treatment + Edaravone + Butylphthalide) and Edaravone group (conventional treatment + Edaravone) randomly, each consisting of 45 cases. The National Institutes of Health Stroke Scale (NIHSS) score and endothelial function index level such as plasma nitric oxide (NO), human endothelin-1 (ET-1), and vascular endothelial cell growth factor (VEGF) were compared before and after treatment between the two groups. The results showed that the MCR of NFCM was evidently inferior to FCM and MRF, and the KI was notably higher relative to the other two algorithms. After treatment, the NIHSS score of the combined treatment group was (9.09 ± 1.86) points and that of Edaravone group was (14.97 ± 3.44) points, with evident difference between the two groups ( P < 0.05 ). After treatment, the NO of the combined treatment was (54.63 ± 4.85), and that of Edaravone group was (41.54 ± 5.27), which was considerably different ( P < 0.01 ), and the VEGF and ET-1 of combined treatment group were greatly inferior to Edaravone group ( P < 0.01 ). It was revealed that the novel algorithm based on FCM can obtain more favorable quality and segmentation accuracy of MRI images. Moreover, Butylphthalide combined with Edaravone treatment can effectively improve nerve function, vascular endothelial function, and short-term prognosis in ACI, which was safe and worthy of clinical adoption.
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Koren-Michowitz, Maya, Batia Avni, Irma Zur, Yulia Volcheck, Naomi Rahimi-Levene, Victor Dishy, Ahuva Golik, and Abraham Kornberg. "Endothelial Function in Patients with Essential Thrombocytosis." Blood 106, no. 11 (November 16, 2005): 3983. http://dx.doi.org/10.1182/blood.v106.11.3983.3983.
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Abstract Essential thrombocytosis (ET) is a myeloproliferative disorder whose main complication is thrombothic events. Reduction of platelet count is associated with a decrease in the risk for thrombosis. Recently it was shown that although anagrelide and hydroxyurea lower platelet counts to the same extent, hydroxyurea decreased the rate of arterial thrombosis and increased the rate of venous thrombosis compared to anagrelide. The reason for the different effects is unknown. The endothelium has important antithrombotic properties. Therefore, we hypothesized that hydroxyurea and anagrelide may have different effects on endothelial function in patients with ET. Thirty patients with ET were studied; 12 treated with anagrelide and 18 with hydroxyurea. Endothelial function was assessed using a semi-automated pulse wave analysis system (SphygmoCor PVX, AtCor Medical, Sydney Australia). Pulse wave is recorded at the radial artery. Using a validated transfer function, the following variables are determined: central systolic blood pressure (CSBP); augmentation index (AIx), a reflection of arterial stiffness; augmentation index adjusted for heart rate (AIx@75). Measurements were taken at baseline, after inhalation of terbutaline 500 mcg (representing endothelial dependent vasodilation due to NO synthesis), and after sublingual nitroglycerine 400 mcg (representing endothelial independent vasodilation). The difference between baseline AIx and maximum response after terbutaline and nitroglycerine are given as EDV (endothelial dependent vasodilation) and EIV (endothelial independent vasodilation), respectively. There was no difference between the two groups of patients with regard to disease duration, age, gender, prior thrombotic events and risk factors for atherosclerosis including BMI, hyperlipidemia, diabetes mellitus, smoking history and hypertension. Mean Hct and platelet count was the same in both groups of patients. However, WBC and neutrophil counts were lower in patients treated with hydroxyurea compared to the patients treated with anagrelide (WBC 6.2±1.4 K/μl vs. 8.4±3.4 K/μl, p=0.07, neutrophils 4.0±1.2 K/μl vs. 6.3±2.9 K/μl, p=0.05). Parameters of arterial stiffness and endothelial function did not differ significantly between the two groups of patients (Table 1). There was no correlation between platelet count and endothelial function, however a correlation between CSBP and age was found (R= 0.615 p<0.001). In conclusion: our preliminary results do not support a different effect for hydroxyurea and anagrelide on arterial stiffness and endothelial function in patients with ET. In accordance with previous reports we found a lower neutrophil count in the group of patients on hydroxyurea therapy. This may affect the interaction between neutrophils and the vessel wall thereby decreasing the rate of arterial thrombosis. Table 1 Therapy (N) Anagrelide (12) Hydroxyurea (18) CSBP mmHg 120±14 122±21 AIx % 26±12 33±11 AIx@75 % 25±10 27±10 EDV % −2±8.6 0.6±7.5 EIV % −11±9 −15±7
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Phillips, Shane A., Kimberly R. Pechman, Ellen C. Leonard, Jessica L. Friedrich, Jing-Tan Bian, Alisa G. Beal, and David P. Basile. "Increased ANG II sensitivity following recovery from acute kidney injury: role of oxidant stress in skeletal muscle resistance arteries." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 298, no. 6 (June 2010): R1682—R1691. http://dx.doi.org/10.1152/ajpregu.00448.2009.
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Ischemia-reperfusion (I/R)-induced acute kidney injury (AKI) results in prolonged impairment of peripheral (i.e., nonrenal) vascular function since skeletal muscle resistance arteries derived from rats 5 wk post-I/R injury, show enhanced responses to ANG II stimulation but not other constrictors. Because vascular superoxide increases ANG II sensitivity, we hypothesized that peripheral responsiveness following recovery from AKI was attributable to vascular oxidant stress. Gracilis arteries (GA) isolated from post-I/R rats (∼5 wk recovery) showed significantly greater superoxide levels relative to sham-operated controls, as detected by dihydroeithidium, which was further augmented by acute ANG II stimulation in vitro. Hydrogen peroxide measured by dichlorofluorescein was not affected by ANG II. GA derived from postischemic animals manifested significantly greater constrictor responses in vitro to ANG II than GA from sham-operated controls. The addition of the superoxide scavenging reagent Tempol (10−5 M) normalized the response to values similar to sham-operated controls. Apocynin (10−6 M) and endothelial denudation nearly abrogated all ANG II-stimulated constrictor activity in GA from post-AKI rats, suggesting an important role for an endothelial-derived source of peripheral oxidative stress. Apocynin treatment in vivo abrogated GA oxidant stress and attenuated ANG II-induced pressor responses post-AKI. Interestingly, gene expression studies in GA vessels indicated a paradoxical reduction in NADPH oxidase subunit and AT1-receptor genes and no effect on several antioxidant genes. Taken together, this study demonstrates that AKI alters peripheral vascular responses by increasing oxidant stress, likely in the endothelium, via an undefined mechanism.
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Viñas, Jose L., Christopher J. Porter, Adrianna Douvris, Matthew Spence, Alex Gutsol, Joseph A. Zimpelmann, Karishma Tailor, Pearl A. Campbell, and Kevin D. Burns. "Sex diversity in proximal tubule and endothelial gene expression in mice with ischemic acute kidney injury." Clinical Science 134, no. 14 (July 2020): 1887–909. http://dx.doi.org/10.1042/cs20200168.
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Abstract Female sex protects against development of acute kidney injury (AKI). While sex hormones may be involved in protection, the role of differential gene expression is unknown. We conducted gene profiling in male and female mice with or without kidney ischemia–reperfusion injury (IRI). Mice underwent bilateral renal pedicle clamping (30 min), and tissues were collected 24 h after reperfusion. RNA-sequencing (RNA-Seq) was performed on proximal tubules (PTs) and kidney endothelial cells. Female mice were resistant to ischemic injury compared with males, determined by plasma creatinine and neutrophil gelatinase-associated lipocalin (NGAL), histologic scores, neutrophil infiltration, and extent of apoptosis. Sham mice had sex-specific gene disparities in PT and endothelium, and male mice showed profound gene dysregulation with ischemia–reperfusion compared with females. After ischemia PTs from females exhibited smaller increases compared with males in injury-associated genes lipocalin-2 (Lcn2), hepatitis A virus cellular receptor 1 (Havcr1), and keratin 18 (Krt18), and no up-regulation of SRY-Box transcription factor 9 (Sox9) or keratin 20 (Krt20). Endothelial up-regulation of adhesion molecules and cytokines/chemokines occurred in males, but not females. Up-regulated genes in male ischemic PTs were linked to tumor necrosis factor (TNF) and Toll-like receptor (TLR) pathways, while female ischemic PTs showed up-regulated genes in pathways related to transport. The data highlight sex-specific gene expression differences in male and female PTs and endothelium before and after ischemic injury that may underlie disparities in susceptibility to AKI.
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Wang, Wei, Einath Zolty, Sandor Falk, Sandra Summer, Robert Stearman, Mark Geraci, and Robert Schrier. "Prostacyclin in endotoxemia-induced acute kidney injury: cyclooxygenase inhibition and renal prostacyclin synthase transgenic mice." American Journal of Physiology-Renal Physiology 293, no. 4 (October 2007): F1131—F1136. http://dx.doi.org/10.1152/ajprenal.00212.2007.
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Sepsis-related acute kidney injury (AKI) is the leading cause of AKI in intensive care units. Endotoxin is a primary initiator of inflammatory and hemodynamic consequences of sepsis and is associated with experimental AKI. The present study was undertaken to further examine the role of the endothelium, specifically prostacyclin (PGI2), in the pathogenesis of endotoxemia-related AKI. A low dose of endotoxin (LPS, 1 mg/kg) in wild-type (WT) mice was associated with stable glomerular filtration rate (GFR) (164.0 ± 16.7 vs. 173.3 ± 6.7 μl/min, P = not significant) as urinary excretion of 6-keto-PGF1α, the major metabolite of PGI2, increased. When cyclooxygenase inhibition with indomethacin abolished this rise in 6-keto-PGF1α, the same low dose of LPS significantly decreased GFR (110.7 ± 12.1 vs. 173.3 ± 6.7 μl/min, P < 0.05). The same dose of indomethacin did not alter GFR in WT mice. To further study the role of PGI2 in endotoxemia, renal-specific PGI synthase (PGIs) transgenic (Tg) mice were developed that had increased PGIs expression only in the kidney and increased urinary 6-keto-PGF1α. These Tg mice, however, demonstrated endotoxemia-related AKI with low-dose LPS (1 mg/kg) (GFR: 12.6 ± 3.9 vs. 196.5 ± 21.0 μl/min P < 0.01), which did not alter GFR in WT mice (164.0 ± 16.7 vs. 173.3 ± 6.7 μl/min, P = not significant). An elevation in renal cAMP, however, suggested an activation of the PGI2-cAMP-renin system in these Tg mice. Moreover, angiotensin-converting enzyme inhibition afforded protection against endotoxin-related AKI in these Tg mice. Thus endothelial PGIs-mediated PGI2, as previously shown with endothelial nitric oxide synthase-mediated nitric oxide, contributes to renal protection against endotoxemia-related AKI. This effect may be overridden by excessive activation of the renin-angiotensin system in renal-specific PGIs Tg mice.
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MIURA, Y., C. ITOH, T. MIYAKAWA, K. NAKAI, K. HIRAMORI, K. SERA, and S. FUTATSUGAWA. "SIMULTANEOUS DETERMINATION OF TRACE ELEMENTS IN SERA OF PATIENTS WITH ACUTE MYOCARDIAL INFARCTION BY PIXE -2-." International Journal of PIXE 05, no. 01 (January 1995): 33–38. http://dx.doi.org/10.1142/s012908359500006x.
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Vascular cell adhesion molecule-1 (VCAM-1) is transiently expressed on vascular endothelial cells in response to cytokines. It plays a major role in the adhesion of leucocytes to the endothelium by interaction with its ligand VLA-4, a member of the β1 integrin family. We measured the serum concentration of the soluble VCAM-1 (sVCAM-1) in 114 patients with acute myocardial infarction (AMI) and 37 normal controls by enzyme-linked immunoassay in comparison with trace element concentration. sVCAM-1 levels were markedly higher (mean± SD=833.2±328.9 ng/ml) in the sera of patients with AMI than in normal controls (mean±SD= 549.5±188.8 ng/ml, p<0.001). Using PIXE we also determined concentration of magnesium, manganese, iron, copper, zinc, selenium, and calcium in sera of 43 patients with AMI. There were no clear correlation between the sVCAM-1 concentration and the magnesium, manganese, copper, selenium. But there were significant correlation between the sVCAM-1 concentration and the zinc, calcium (p<0.05).
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MIURA, Y., C. ITOH, T. MIYAKAWA, K. NAKAI, K. HIRAMORI, K. SERA, and S. FUTATSUGAWA. "SIMULTANEOUS DETERMINA TION OF TRACE ELEMENTS IN SERA OF PATIENTS WITH ACUTE MYOCARDIAL INFARCTION BY PIXE -2-." International Journal of PIXE 06, no. 01n02 (January 1996): 233–40. http://dx.doi.org/10.1142/s0129083596000235.
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Vascular cell adhesion molecule-1 (VCAM-1) is transiently expressed on vascular endothelial cells in response to cytokines. It plays a major role in the adhesion of leucocytes to the endothelium by interaction with its ligand VLA-4, a member of the β1 integrin family. We measured the serum concentration of the soluble VCAM-1 (sVCAM-1) in 114 patients with acute myocardial infarction (AMI) and 37 normal controls by enzyme-linked immunoassay in comparison with trace element concentration. sVCAM-1 levels were markedly higher ( mean ± SD =833.2 ± 328.9 ng/ml ) in the sera of patients with AMI than in normal controls ( mean ± SD = 549.5 ± 188.8 ng/ml , p<0.001). Using PIXE we also determined concentration of magnesium, manganese, iron, copper, zinc, selenium, and calcium in sera of 43 patients with AMI. There were no clear correlation between the sVCAM-1 concentration and the magnesium, manganese, copper, selenium, iron. But there were significant correlation between the sVCAM-1 concentration and the zinc, calcium (p<0.05).
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Liu, Zhifeng, Jingjing Ji, Dong Zheng, Lei Su, Tianqing Peng, and Jing Tang. "Protective role of endothelial calpain knockout in lipopolysaccharide-induced acute kidney injury via attenuation of the p38-iNOS pathway and NO/ROS production." Experimental & Molecular Medicine 52, no. 4 (April 2020): 702–12. http://dx.doi.org/10.1038/s12276-020-0426-9.
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Abstract To explore the role of calpain and its signaling pathway in lipopolysaccharide (LPS)-induced acute kidney injury (AKI), animal models of endotoxemia were established by administration of LPS to mice with endothelial-specific Capn4 knockout (TEK/Capn4−/−), mice with calpastatin (an endogenous calpain inhibitor) overexpression (Tg-CAST) and mice with myeloid-specific Capn4 knockout (LYZ/Capn4−/−). Mouse pulmonary microvascular endothelial cells (PMECs) were used as a model of the microvascular endothelium and were stimulated with LPS. Renal function, renal inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) expression, cellular apoptosis, plasma and renal levels of NO and reactive oxygen species (ROS), and phosphorylation of mitogen-activated protein kinase (MAPK) family members (p38, ERK1/2, and JNK1/2) were examined. Moreover, a calpain inhibitor, calpastatin overexpression adenoviruses and MAPK inhibitors were used. Significant renal dysfunction was induced by LPS stimulation, and recovery was observed in TEK/Capn4−/− and Tg-CAST mice but not in LYZ/Capn4−/− mice. Endothelial Capn4 knockout also abrogated the LPS-induced increases in renal iNOS expression, caspase-3 activity and apoptosis and plasma and renal NO and ROS levels but did not obviously affect renal eNOS expression. Moreover, LPS increased both calpain and caspase-3 activity, and only the expression of iNOS in PMECs was accompanied by increased phosphorylation of p38 and JNK. Inhibiting calpain activity or p38 phosphorylation alleviated the increased iNOS expression, NO/ROS production, and cellular apoptosis induced by LPS. These results suggest that endothelial calpain plays a protective role in LPS-induced AKI by inhibiting p38 phosphorylation, thus attenuating iNOS expression and further decreasing NO and ROS overproduction-induced endothelial apoptosis.
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Zhuo, Wei, Xiaomin Song, Hao Zhou, and Yongzhang Luo. "Arginine deiminase modulates endothelial tip cells via excessive synthesis of reactive oxygen species." Biochemical Society Transactions 39, no. 5 (September 21, 2011): 1376–81. http://dx.doi.org/10.1042/bst0391376.
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ADI (arginine deiminase), an enzyme that hydrolyses arginine, has been reported as an anti-angiogenesis agent. However, its molecular mechanism is unclear. We have demonstrated for the first time that ADI modulates the angiogenic activity of endothelial tip cells. By arginine depletion, ADI disturbs actin filament in endothelial tip cells, causing disordered migratory direction and decreased migration ability. Furthermore, ADI induces excessive synthesis of ROS (reactive oxygen species), and activates caspase 8-, but not caspase 9-, dependent apoptosis in endothelial cells. These findings provide a novel mechanism by which ADI inhibits tumour angiogenesis through modulating endothelial tip cells.
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Wang, Wei, Einath Zolty, Sandor Falk, Sandra Summer, Zhu Zhou, Patricia Gengaro, Sarah Faubel, Nicholas Alp, Keith Channon, and Robert Schrier. "Endotoxemia-related acute kidney injury in transgenic mice with endothelial overexpression of GTP cyclohydrolase-1." American Journal of Physiology-Renal Physiology 294, no. 3 (March 2008): F571—F576. http://dx.doi.org/10.1152/ajprenal.00538.2007.
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Endotoxin-related acute kidney injury has been shown to profoundly induce nitric oxide (NO), which activates sympathetic and renin-angiotensin system, resulting in renal vasoconstriction. While vascular muscle cells are known to upregulate inducible NO synthase (iNOS), less is known about the endothelium as a source of NO during endotoxemia. Studies were, therefore, undertaken both in vitro in mouse microvascular endothelial cells and in vivo in transgenic mice with overexpression of endothelial GTP cyclohydrolase, the rate-limiting enzyme for tetrahydrobiopterin, a cofactor for NO synthase. LPS significantly induced endothelial cell iNOS expression and NO concentration in the culture media, with no change in endothelial NO synthase expression. GTP cyclohydrolase-1 transgenic (Tg) mice demonstrated a significant increase in baseline urine NO-to-creatinine ratio and a more significant increase in renal iNOS expression and serum NO levels with LPS treatment compared with the wild-type (WT) mice. Glomerular filtration rate and renal blood flow decreased significantly in Tg mice with 1.0 mg/kg LPS, while no changes were observed in WT with the same dose of LPS. Serum IL-6 levels were significantly higher in Tg compared with WT mice during endotoxemia. The antioxidant tempol improved the glomerular filtration rate in the Tg mice. Thus endothelium can be an important source of iNOS and serum NO concentration during endotoxemia, thereby increasing the sensitivity to AKI. Reactive oxygen species appear to be involved in this acute renal injury in Tg mice during endotoxemia.
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Qiu, Chong-Rong, Qiang Fu, Jian Sui, Qian Zhang, Peng Wei, Yan Wu, Ke Zhu, Yi Lu, and Bing Zong. "Serum Endothelial Cell–Specific Molecule 1 (Endocan) Levels in Patients With Acute Myocardial Infarction and Its Clinical Significance." Angiology 68, no. 4 (September 29, 2016): 354–59. http://dx.doi.org/10.1177/0003319716651349.
Full textAbstract:
Endothelial dysfunction is involved in the process of acute myocardial infarction (AMI), that is, the endothelial cell–specific molecule 1 (ESM-1; endocan) is a novel endothelial dysfunction marker. However, the relationship between patients with AMI and serum ESM-1 levels is not very clear. Patients with AMI (n = 216) and a control group (n = 60) without AMI were included in the study. High-sensitivity C-reactive protein (hsCRP) was measured, and the severity of AMI was assessed by a modified Gensini stenosis scoring system. Serum ESM-1 levels were significantly higher in the AMI group ( P < .05). High-sensitivity C-reactive protein levels were also significantly higher in the AMI group ( P < .05). In patients with AMI, serum ESM-1 levels were not significantly correlated with hsCRP levels. There was no significant correlation between serum ESM-1 level and Gensini score. Our findings suggest that serum ESM-1 levels may be a novel biomarker of endothelial dysfunction in patients with AMI.
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Huang, Lan, Dongming Hou, Meredith A. Thompson, Sarah E. Baysden, W. Christopher Shelley, David A. Ingram, Keith L. March, and Mervin C. Yoder. "Acute Myocardial Infarction in Swine Rapidly and Selectively Releases Highly Proliferative Endothelial Colony Forming Cells (ECFCs) into Circulation." Cell Transplantation 16, no. 9 (October 2007): 887–97. http://dx.doi.org/10.3727/096368907783338181.
Full textAbstract:
We have recently identified endothelial colony forming cells (ECFCs) in human blood and blood vessels, and ECFC are elevated in patients with coronary artery disease. Because pigs are a favored model for studying myocardial ischemia, we questioned whether ECFCs also exist in swine and whether myocardial ischemia would alter the number of ECFC in circulation. ECFCs were present in circulating blood and aortic endothelium of healthy pigs. In pigs with an acute myocardial infarction (AMI) (n = 9), the number of circulating ECFC was markedly increased compared to sham control pigs (15 ± 6 vs. 1 ± 1 colonies/100 cc blood, p < 0.05). Moreover, the percentage of circulating high proliferative potential ECFCs (HPP-ECFCs) was significantly increased following AMI induction compared to sham control (38.4 ± 5.8% vs. 0.4 ± 0.4%, p < 0. 05) and to baseline (38.4 ± 5.8% vs. 2.4 ± 2.4%, p < 0. 05) blood samples. This is the first study to report that ECFCs are present in blood and aorta in healthy pigs and that the number and distribution of circulating ECFCs is altered following AMI. Because circulating ECFC are also altered in human subjects with severe coronary artery disease, the pig model of AMI may be an excellent preclinical model to test the role of ECFC in the pathophysiology of AMI.
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Gąsecka, Aleksandra, Kinga Pluta, Katarzyna Solarska, Bartłomiej Rydz, Ceren Eyileten, Marek Postula, Edwin van der Pol, et al. "Plasma Concentrations of Extracellular Vesicles Are Decreased in Patients with Post-Infarct Cardiac Remodelling." Biology 10, no. 2 (January 30, 2021): 97. http://dx.doi.org/10.3390/biology10020097.
Full textAbstract:
Background, the mechanisms underlying left ventricular remodelling (LVR) after acute myocardial infarction (AMI) remain obscure. In the course of AMI, blood cells and endothelial cells release extracellular vesicles (EVs). We hypothesized that changes in EV concentrations after AMI may underlie LVR. Methods, plasma concentrations of EVs from endothelial cells (CD146+), erythrocytes (CD235a+), leukocytes (CD45+), platelets (CD61+), activated platelets (P-selectin+), and EVs exposing phosphatidylserine after AMI were determined by flow cytometry in 55 patients with the first AMI. LVR was defined as an increase in left ventricular end-diastolic volume by 20% at 6 months after AMI, compared to baseline. Results, baseline concentrations of EVs from endothelial cells, erythrocytes and platelets were lower in patients who developed LVR (p ≤ 0.02 for all). Concentrations of EVs from endothelial cells and erythrocytes were independent LVR predictors (OR 8.2, CI 1.3–54.2 and OR 17.8, CI 2.3–138.6, respectively) in multivariate analysis. Combining the three EV subtypes allowed to predict LVR with 83% sensitivity and 87% specificity. Conclusions, decreased plasma concentrations of EVs from endothelial cells, erythrocytes and platelets predict LVR after AMI. Since EV release EVs contributes to cellular homeostasis by waste removal, decreased concentrations of EVs may indicate dysfunctional cardiac homeostasis after AMI, thus promoting LVR.
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Kosacka, Monika, and Anna Brzecka. "Endothelin-1 and LOX-1 as Markers of Endothelial Dysfunction in Obstructive Sleep Apnea Patients." International Journal of Environmental Research and Public Health 18, no. 3 (February 1, 2021): 1319. http://dx.doi.org/10.3390/ijerph18031319.
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Introduction: The search of biochemical markers of endothelial dysfunction: lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)—involved in atherosclerotic plaques formation—and endothelin-1 (ET-1)—potent vasoconstrictor-might help in detecting obstructive sleep apnea (OSA) patients at high risk of cardiovascular diseases. Material and Methods: In 71 OSA patients (apnoea/hypopnoea index, AHI 28.2 ± 17.9/hour) and in 21 healthy controls the serum levels of LOX-1 and ET-1 were measured. Results: There were increased levels of ET-1 (1.58 ± 0.65 vs. 1.09 ± 0.38 pg/mL; p < 0.001) but not of LOX-1 in OSA patients as compared with healthy controls. In the patients’ group ET-1 levels negatively correlated with serum LDL levels. LOX-1 levels positively correlated with fasting glucose levels and were higher in the patients with than without diabetes. Neither ET-1 nor LOX-1 correlated with OSA severity. In mild OSA patients, there was a negative correlation between LOX-1 and mean arterial oxygen saturation during sleep. In severe OSA patients, there was a positive correlation between LOX-1 levels and uric acid. Conclusion: There is endothelial dysfunction in OSA patients as indicated by increased serum levels of ET-1 and possibly endothelial dysfunction in diabetic OSA patients as indicated by increased serum levels of LOX-1 and its correlation with fasting glucose levels.
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Yang, Yi, Shuling Hu, Xiuping Xu, Jinze Li, Airan Liu, Jibin Han, Songqiao Liu, Ling Liu, and Haibo Qiu. "The Vascular Endothelial Growth Factors-Expressing Character of Mesenchymal Stem Cells Plays a Positive Role in Treatment of Acute Lung InjuryIn Vivo." Mediators of Inflammation 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/2347938.
Full textAbstract:
Recently, mesenchymal stem cells (MSC) have been proved to be beneficial in acute respiratory distress syndrome (ARDS). Vascular endothelial growth factor (VEGF) is an important angiogenesis factor that MSC release. However, the precise role of VEGF-expressing character of MSC in the MSC treatment for ARDS remains obscure. Here, we firstly knocked down the gene VEGF in MSC (MSC-ShVEGF) with lentiviral transduction. Then we injected the MSC-ShVEGF to rats with lipopolysaccharide-induced acute lung injury (ALI) via the tail vein. Data showed that MSC transplantation significantly increased VEGF levels in the lung, reduced lung permeability, protected lung endothelium from apoptosis, facilitated VE-cadherin recovery, controlled inflammation, and attenuated lung injury. However, VEGF gene knockdown in MSC led to relatively insufficient VEGF expression in the injured lung and significantly diminished the therapeutic effects of MSC on ALI, suggesting an important role of VEGF-expressing behavior of MSC in the maintenance of VEGF in the lung and the MSC treatment for ALI. Hence, we conclude that MSC restores the lung permeability and attenuates lung injury in rats with ALI in part by maintaining a “sufficient” VEGF level in the lung and the VEGF-expressing character of MSC plays a positive role in the therapeutic effects of MSC on ARDS.