Journal articles on the topic 'ENOS protein expression'
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1
ARRIERO, MARÍA M., JUAN A. RODRÍGUEZ-FEO, ÁNGEL CELDRÁN, LOURDES SÁNCHEZ DE MIGUEL, FERNANDO GONZÁLEZ-FERNÁNDEZ, JOSÉ FORTES, ANA REYERO, et al. "Expression of Endothelial Nitric Oxide Synthase in Human Peritoneal Tissue." Journal of the American Society of Nephrology 11, no. 10 (October 2000): 1848–56. http://dx.doi.org/10.1681/asn.v11101848.
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Abstract. Changes in the expression of endothelial nitric oxide synthase (eNOS) in the peritoneum could be involved in the peritoneal dysfunction associated with peritoneal inflammation. Demonstrated recently in bovine endothelial cells was the existence of cytosolic proteins that bind to the 3′-untranslated region (3′-UTR) of eNOS mRNA and could be implicated in eNOS mRNA stabilization. The present work demonstrates that eNOS protein is expressed in human endothelial and mesothelial peritoneal cells. Escherichia coli lipopolysaccharide shortened the half-life of eNOS message, reducing eNOS protein expression in peritoneal mesothelial and endothelial cells. Moreover, under basal conditions, human peritoneal samples expressed cytosolic proteins that bind to the 3′-UTR of eNOS mRNA. The cytosolic proteins that directly bind to 3′-UTR were identified as a 60-kD protein. After incubation of human peritoneal samples with lipopolysaccharide, the binding activity of the cytosolic 60-kD protein increased in a time-dependent manner. Studies are now necessary to determine the involvement of this 60-kD protein in the regulation of eNOS expression in peritoneal cells and particularly its involvement in the peritoneal dysfunction associated with inflammatory reactions.
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Grazul-Bilska, Anna T., Chainarong Navanukraw, Mary Lynn Johnson, Daniel A. Arnold, Lawrence P. Reynolds, and Dale A. Redmer. "Expression of endothelial nitric oxide synthase in the ovine ovary throughout the estrous cycle." Reproduction 132, no. 4 (October 2006): 579–87. http://dx.doi.org/10.1530/rep-06-0009.
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This study was conducted to evaluate the expression of endothelial nitric oxide synthase (eNOS) in ovarian follicles and corpora lutea (CL) throughout the estrous cycle in sheep. Three experiments were conducted to (1) immunolocalize eNOS protein, (2) determine expression of mRNA for eNOS and its receptor guanylate cyclase 1 soluble β3 (GUCY1B3), and (3) co-localize eNOS and vascular endothelial growth factor (VEGF) proteins in the follicles and/or CL throughout the estrous cycle. In experiment 1, ovaries were collected from ewes treated with FSH, to induce follicular growth or atresia. In experiment 2, ovaries were collected from ewes treated with FSH and hCG to induce follicular growth and ovulation. In experiment 3, ovaries were collected from superovulated ewes to generate multiple CL on days 2, 4, 10, and 15 of the estrous cycle. In experiments 1 and 2, the expression of eNOS protein was detected in the blood vessels of the theca externa and interna of healthy ovarian follicles. However, in early and advanced atretic follicles, eNOS protein expression was absent or reduced. During the immediate postovulatory period, eNOS protein expression was detected in thecal-derived cells that appeared to be invading the granulosa layer. Expression of eNOS mRNA tended to increase in granulosa cells at 12 and 24 h, and in theca cells 48 h after hCG injection. In experiment 3, eNOS protein was located in the blood vessels of the CL during the estrous cycle. Dual localization of eNOS and VEGF proteins in the CL demonstrated that both were found in the blood vessels.
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Ruiz-Holst, C., B. Bölck, A. Ghanem, K. Tiemann, S. Brokat, V. Regitz-Zagrosek, W. Bloch, Robert H. G. Schwinger, and K. Brixius. "eNOS phosphorylation and translocation are altered in male but not female mice by increased activation of the Gαq protein." Canadian Journal of Physiology and Pharmacology 88, no. 2 (February 2010): 121–29. http://dx.doi.org/10.1139/y09-115.
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Little is known about sex-dependent physiological and pathophysiological differences in cardiac endothelial nitric oxide synthase (eNOS) expression and activation. Therefore, we investigated cardiac morphology and eNOS protein expression, including its translocation-dependent activation and phosphorylation, in cardiac tissue of male and female wild-type mice and transgenic heart-failure mice having a cardiac-specific, 5-fold overexpression of the Gαq protein. In addition, we measured calcineurin protein expression. Heart-to-body weight ratio was increased in Gαq mice. Female wild-type mice showed higher eNOS protein expression and activation (translocation and phosphorylation) than did wild-type males. In cardiac tissue of Gαq mice, these sex-dependent differences remained or were enhanced. Protein expression of the catalytic subunit calcineurin A, which has been shown to dephosphorylate eNOS, was higher in wild-type males than in wild-type females. These differences were increased in the Gαq mice model. We conclude that sex differences exist in cardiac eNOS protein expression and phosphorylation. Increased activation of the Gαq protein appears to alter eNOS protein expression and phosphorylation only in males.
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Li, Dechun, Victor E. Laubach, and Roger A. Johns. "Upregulation of lung soluble guanylate cyclase during chronic hypoxia is prevented by deletion of eNOS." American Journal of Physiology-Lung Cellular and Molecular Physiology 281, no. 2 (August 1, 2001): L369—L376. http://dx.doi.org/10.1152/ajplung.2001.281.2.l369.
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Hypoxia upregulates endothelial (e) nitric oxide synthase (NOS), but how eNOS affects soluble guanylate cyclase (sGC) protein expression in hypoxia-induced pulmonary hypertension is unknown. Wild-type (WT), eNOS-deficient [eNOS(−/−)], and inducible NOS (iNOS)-deficient [iNOS(−/−)] mice were used to investigate the effects of lack of NO from different NOS isoforms on sGC activity and protein expression and its relationship to the muscularization of the pulmonary vasculature. After 6 days of hypoxic exposure (10% O2), the ratios of the right ventricle to left ventricle + septum weight (RV/LV+S) and right ventricle weight to body weight, the lung sGC activity, and vascular muscularization were determined, and protein analysis for eNOS, iNOS, and sGC was performed. Results demonstrated that there were significant increases of RV/LV+S in all animals treated with hypoxia. In hypoxic WT and iNOS(−/−) mice, eNOS and sGC α1- and β1-protein increased twofold; cGMP levels and the number of muscularized vessels also increased compared with hypoxic eNOS(−/−) mice. There was a twofold increase of iNOS protein in WT and eNOS(−/−) mice, and the basal iNOS protein concentration was higher in eNOS(−/−) mice than in WT mice. In contrast, the eNOS(−/−) mouse lung showed no eNOS protein expression, lower cGMP concentrations, and no change of sGC protein levels after hypoxic exposure compared with its normoxic controls ( P > 0.34). These results suggest that eNOS, but not iNOS, is a major regulator of sGC activity and protein expression in the pulmonary vasculature.
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Kim, Hee Youn, and Dong Sup Lee. "A role for phosphodiesterase type 5 inhibitors in remodelling the urinary bladder after radiation exposure." PLOS ONE 15, no. 11 (November 9, 2020): e0242006. http://dx.doi.org/10.1371/journal.pone.0242006.
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Minimizing the toxicity of radiotherapy is challenging. We investigated the effects of a phosphodiesterase type-5 inhibitor (PDE5I) on the urinary bladder after pelvic radiotherapy. Eight rats were assigned to each group (group 1: control; group 2: radiation; group 3: radiation plus PDE5I). Radiation dose was 10 Gy/one fraction. Udenafil (20 mg/kg, daily for 4 weeks) was administered in group 3. Cystometry was performed 4 weeks after treatment, followed by real-time PCR for PDE5, vascular endothelial growth factor (VEGF), and endothelial nitric oxide synthase (eNOS) mRNA, western blotting for PDE5, cyclic GMP-dependent protein kinase (PRKG), VEGF164, Akt, eNOS and NADPH oxidase (NOX)-2 proteins, and immunohistochemistry for eNOS. The expression of both VEGF mRNA and eNOS mRNA was higher in group 3 than in group 2. VEGF and eNOS protein expression improved with PDE5I treatment. Akt protein phosphorylation was higher in group 3 than in group 2, but NOX-2 protein expression was lower in group 3 than in group 2. Immunohistochemistry showed that the mean density of arterioles expressing eNOS was higher in group 3 than in group 2. Cystometry revealed that the intercontraction interval was remarkably longer in group 3 than in group 2 but that the maximal voiding pressure was higher in group 2 than in group 3. Daily treatment with a PDE5I after radiotherapy may prevent bladder storage dysfunction, potentially due to its effects on vasodilation and angiogenesis and through minimizing tissue oxidative damage by means of the VEGF/Akt/eNOS pathway.
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North, A. J., K. S. Lau, T. S. Brannon, L. C. Wu, L. B. Wells, Z. German, and P. W. Shaul. "Oxygen upregulates nitric oxide synthase gene expression in ovine fetal pulmonary artery endothelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 270, no. 4 (April 1, 1996): L643—L649. http://dx.doi.org/10.1152/ajplung.1996.270.4.l643.
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Nitric oxide (NO) is critically involved in oxygen-mediated pulmonary vasodilatation in the fetus and newborn. We determined the effects of prolonged alterations in oxygenation on endothelial NO synthase (eNOS) gene expression in early passage ovine fetal intrapulmonary artery endothelial cells (PAEC). PAEC were exposed to PO2 = 50 or 150 mmHg for 48 h, and eNOS protein expression was evaluated by immunoblot analysis. eNOS protein expression was 2.7-fold greater at higher oxygen tension; eNOS upregulation was also evident after 24 h. Inducible NOS protein was not detectable by immunoblot at either level of oxygenation. In the lung, the effect of oxygen on eNOS expression may be specific to the endothelium, as eNOS expression in bronchiolar epithelial cells of Clara cell lineage was not altered by varying oxygen tension. The oxygen-related increase in eNOS protein in the fetal PAEC was associated with 2.5-fold greater NOS enzymatic activity. In parallel, there was a 2.8-fold rise in eNOS mRNA abundance. Thus eNOS gene expression in ovine fetal PAEC is upregulated by oxygen, and this is mediated at the level of gene transcription or mRNA stability. This process may play an important role in oxygen modulation of pulmonary vasomotor tone in the fetus and newborn.
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Ríos, Nisa Buset, Francisco Rodríguez Esparragón, and José C. Rodríguez Pérez. "Telmisartan-induced eNOS gene expression is partially independent of its PPAR-gamma agonist property." Clinical & Investigative Medicine 35, no. 2 (April 1, 2012): 55. http://dx.doi.org/10.25011/cim.v35i2.16289.
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Purpose: Telmisartan, an angiotensin II receptor blocker (ARB), also acts as an activator of peroxisome proliferator-activated receptor-gamma (PPAR-gamma; PPAR-γ). Several studies have explored the PPAR-γ-endothelial nitric oxide synthase (eNOS) pathway associated with improvement of endothelial function by telmisartan. The ability of telmisartan to induce gene expression and protein level of eNOS and PPARγ in adipocytes was investigated. Methods: Expression of aP2, PPARγ, eNOS and iNOS genes were measured using the quantitative real-time polymerase chain reaction. The changes, at the protein level, were explored by Western blot, which evaluated the native and phosphorylated eNOS forms, eNOS-Ser1177 and eNOS-Thr495. Results: Adipocytes, exposed to telmisartan, exhibited an increase in PPARγ gene expression but a decrease in protein level. Nonetheless, after the exposure to telmisartan, eNOS-Ser1177 phosphorylation, associated with eNOS activity increment, reached its highest value while eNOS-Thr495 phosphorylation, involved in the inhibition of eNOS activity, showed its lowest value. Conclusion: The results suggest that telmisartan preserves eNOS activity via a mechanism that is partially independent of the PPARγ-eNOS pathway in adipocytes.
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de Frutos, Trinidad, Lourdes Sánchez de Miguel, Margarita García-Durán, Fernando González-Fernández, Juan A. Rodríguez-Feo, Mercedes Montón, José Guerra, Jerónimo Farré, Santos Casado, and Antonio López-Farré. "NO from smooth muscle cells decreases NOS expression in endothelial cells: role of TNF-α." American Journal of Physiology-Heart and Circulatory Physiology 277, no. 4 (October 1, 1999): H1317—H1325. http://dx.doi.org/10.1152/ajpheart.1999.277.4.h1317.
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Despite the evidence that cytokines stimulate nitric oxide (NO) production by inducible nitric oxide synthase (iNOS), several reports recently demonstrated that the hypotensive response related to endothelial nitric oxide synthase (eNOS) activity could be inhibited by the same cytokines. The aim of the present work was to analyze whether NO generated by vascular smooth muscle cells (VSMC) could modify eNOS protein expression in endothelial cells. Bovine aortic endothelial cells (BAEC) and bovine VSMC (BVSMC) in coculture were used for the study. Interleukin-1β (IL-1β, 10 ng/ml)-treated BVSMC, which expressed iNOS protein, decreased eNOS protein expression in BAEC. The presence of NO antagonists N ω-nitro-l-arginine methyl ester (10−3 mol/l) or N G-monomethyl-l-arginine (10−3 mol/l) prevented the decrease in eNOS protein expression induced by IL-1β-treated BVSMC. Surprisingly, two different NO donors, 3-morpholinosydnonimine (10−4 mol/l) and S-nitroso- N-acetyl-d,l-penicillamine (10−4 mol/l), failed to modify eNOS expression in BAEC, suggesting the existence of a diffusible mediator released from IL-1β-treated BVSMC that acts on endothelial cells by reducing eNOS expression. The presence of NO antagonists reduced tumor necrosis factor-α (TNF-α) production by IL-1β-stimulated BVSMC. This effect was also produced in the presence of a protein kinase G inhibitor, guanosine-5′-O-(2-thiodiphosphate) trilithium salt. A polyclonal antibody against TNF-α prevented eNOS expression in the BAEC-BVSMC coculture. In conclusion, NO by itself failed to modify eNOS protein expression in endothelial cells but increased TNF-α generation by IL-1β-stimulated BVSMC and, in this way, reduced eNOS expression in the endothelium.
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Shaul, P. W., I. S. Yuhanna, Z. German, Z. Chen, R. H. Steinhorn, and F. C. Morin. "Pulmonary endothelial NO synthase gene expression is decreased in fetal lambs with pulmonary hypertension." American Journal of Physiology-Lung Cellular and Molecular Physiology 272, no. 5 (May 1, 1997): L1005—L1012. http://dx.doi.org/10.1152/ajplung.1997.272.5.l1005.
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Nitric oxide (NO), produced by endothelial (e) NO synthase (NOS), is critically involved in the cardiopulmonary transition from fetal to neonatal life. We have previously shown that NO-dependent relaxation is attenuated in intrapulmonary arteries from fetal lambs with pulmonary hypertension (PHT) created by prenatal ligation of the ductus arteriosus. In the present study, we determined whether this is due to altered pulmonary eNOS expression. eNOS and neuronal NOS (nNOS) protein expression were assessed in lungs from near-term control lambs and PHT lambs that underwent ductal ligation 10 days earlier. eNOS protein expression was decreased 49% in PHT lung. In contrast, nNOS protein abundance was unchanged. NOS enzymatic activity was also diminished in PHT vs. control lung (60 +/- 3 vs. 110 +/- 7 fmol.mg protein-1.min-1, respectively). Paralleling the declines in eNOS protein and NOS enzymatic activity, eNOS mRNA abundance was decreased 64% in PHT lung. Thus pulmonary eNOS gene expression is attenuated in the lamb model of fetal PHT. Because NO modulates both vasodilation and vascular smooth muscle growth, diminished eNOS expression may contribute to both the abnormal vasoreactivity and the excessive muscularization of the pulmonary circulation in fetal PHT.
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Parker, Thomas A., Timothy D. le Cras, John P. Kinsella, and Steven H. Abman. "Developmental changes in endothelial nitric oxide synthase expression and activity in ovine fetal lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 278, no. 1 (January 1, 2000): L202—L208. http://dx.doi.org/10.1152/ajplung.2000.278.1.l202.
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Endothelial nitric oxide (NO) synthase (eNOS) produces NO, which contributes to vascular reactivity in the fetal lung. Pulmonary vasoreactivity develops during late gestation in the ovine fetal lung, during the period of rapid capillary and alveolar growth. Although eNOS expression peaks near birth in the fetal rat, lung capillary and distal air space development occur much later than in the fetal lamb. To determine whether lung eNOS expression in the lamb differs from the timing and pattern reported in the rat, we measured eNOS mRNA and protein by Northern and Western blot analyses and NOS activity by the arginine-to-citrulline conversion assay in lung tissue from fetal, newborn, and maternal sheep. Cellular localization of eNOS expression was determined by immunohistochemistry. eNOS mRNA, protein, and activity were detected in samples from all ages, and eNOS was expressed predominantly in the vascular endothelium. Lung eNOS mRNA expression increases from low levels at 70 days gestation to peak at 113 days and remains high for the rest of fetal life. Newborn eNOS mRNA expression does not change from fetal levels but is lower in the adult ewe. Lung eNOS protein expression in the fetus rises and peaks at 118 days gestation but decreases before birth. eNOS protein expression rises in the newborn period but is lower in the adult. Lung NOS activity also peaks at 118 days gestation in the fetus before falling in late gestation and remaining low in the newborn and adult. We conclude that the pattern of lung eNOS expression in the sheep differs from that in the rat and may reflect species-related differences in lung development. We speculate that the rise in fetal lung eNOS may contribute to the marked lung growth and angiogenesis that occurs during the same period of time.
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Solhaug, Michael J., Usa Kullaprawithaya, Xui Q. Dong, and Ke-Wen Dong. "Expression of endothelial nitric oxide synthase in the postnatal developing porcine kidney." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 280, no. 5 (May 1, 2001): R1269—R1275. http://dx.doi.org/10.1152/ajpregu.2001.280.5.r1269.
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The postnatal pattern of renal endothelial nitric oxide synthase (eNOS) is unknown. The purpose of this study was to characterize eNOS expression during maturation and compare this to neuronal NOS (nNOS). The experiments measured whole kidney eNOS mRNA expression by RT-PCR and protein content by Western blot, as well as cortical and medullary protein content in piglets at selected postnatal ages and in adult pigs. Whole kidney eNOS mRNA was compared with nNOS. Whole kidney eNOS expression decreased from the newborn to its lowest at 7 days, returning by 14 days to adult levels. This eNOS mRNA pattern contrasted with nNOS, which was highest at birth, and progressively decreased to its lowest level in the adult. At birth, cortical eNOS protein was greater than medullary, contrasting with the adult pattern of equivalent levels. In conclusion eNOS is developmentally regulated during early renal maturation and may critically participate in renal function during this period. The eNOS developmental pattern differs from nNOS, suggesting that these isoforms may have different regulatory factors and functional contributions in the postnatal kidney.
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Si, Hongwei, Jie Yu, Hongling Jiang, Hazel Lum, and Dongmin Liu. "Phytoestrogen Genistein Up-Regulates Endothelial Nitric Oxide Synthase Expression Via Activation of cAMP Response Element-Binding Protein in Human Aortic Endothelial Cells." Endocrinology 153, no. 7 (June 5, 2012): 3190–98. http://dx.doi.org/10.1210/en.2012-1076.
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We previously reported that genistein, a phytoestrogen, up-regulates endothelial nitric oxide synthase (eNOS) and prevents hypertension in rats that are independent of estrogen signaling machinery. However, how genistein regulates eNOS expression is unknown. In the present study, we show that genistein enhanced eNOS expression and NO synthesis in primary human aortic endothelial cells. Inhibition of extracellular signal regulated kinase, phosphoinositol-3 kinase, or protein kinase C did not affect genistein-enhanced eNOS expression and NO synthesis. However, chemical inhibition of protein kinase A (PKA) or adenoviral transfer of the specific endogenous PKA inhibitor gene completely abolished PKA activity and genistein-stimulated eNOS expression and NO production. Accordingly, genistein induced PKA activity and subsequent phosphorylation of cAMP response element (CRE)-binding protein (CREB) at Ser133. Suppression of CREB by small interfering RNA transfection abolished genistein-enhanced eNOS expression and NO production. Consistently, deletion of the CRE site within human eNOS promoter eliminated genistein-stimulated eNOS promoter activity. These findings provide the first evidence to our knowledge that genistein may play a beneficial role in vascular function through targeting the PKA/CREB/eNOS/NO signaling pathway.
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Sud, Neetu, Stephen Wedgwood, and Stephen M. Black. "Protein kinase Cδ regulates endothelial nitric oxide synthase expression via Akt activation and nitric oxide generation." American Journal of Physiology-Lung Cellular and Molecular Physiology 294, no. 3 (March 2008): L582—L591. http://dx.doi.org/10.1152/ajplung.00353.2007.
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In this study, we explore the roles of the delta isoform of PKC (PKCδ) in the regulation of endothelial nitric oxide synthase (eNOS) activity in pulmonary arterial endothelial cells isolated from fetal lambs (FPAECs). Pharmacological inhibition of PKCδ with either rottlerin or with the peptide, δV1-1, acutely attenuated NO production, and this was associated with a decrease in phosphorylation of eNOS at Ser1177 (S1177). The chronic effects of PKCδ inhibition using either rottlerin or the overexpression of a dominant negative PKCδ mutant included the downregulation of eNOS gene expression that was manifested by a decrease in both eNOS promoter activity and protein expression after 24 h of treatment. We also found that PKCδ inhibition blunted Akt activation as observed by a reduction in phosphorylated Akt at position Ser473. Thus, we conclude that PKCδ is actively involved in the activation of Akt. To determine the effect of Akt on eNOS signaling, we overexpressed a dominant negative mutant of Akt and determined its effect of NO generation, eNOS expression, and phosphorylation of eNOS at S1177. Our results demonstrated that Akt inhibition was associated with decreased NO production that correlated with reduced phosphorylation of eNOS at S1177, and decreased eNOS promoter activity. We next evaluated the effect of endogenously produced NO on eNOS expression by incubating FPAECs with the eNOS inhibitor 2-ethyl-2-thiopseudourea (ETU). ETU significantly inhibited NO production, eNOS promoter activity, and eNOS protein levels. Together, our data indicate involvement of PKCδ-mediated Akt activation and NO generation in maintaining eNOS expression.
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Harris, M. Brennan, Michele A. Blackstone, Hong Ju, Virginia J. Venema, and Richard C. Venema. "Heat-induced increases in endothelial NO synthase expression and activity and endothelial NO release." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 1 (July 2003): H333—H340. http://dx.doi.org/10.1152/ajpheart.00726.2002.
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Endothelial nitric oxide (NO) synthase (eNOS) is regulated by heat shock protein 90 (HSP90), a heat-inducible protein; however, the effect of heat shock on eNOS expression and eNO release is unknown. Bovine aortic endothelial cells were incubated for 1 h at 37°C, 42°C, or 45°C and cell lysates were evaluated with the use of Western blotting. We observed a 2.1 ± 0.1-fold increase in eNOS protein content, but no change in HSP90 content, HSP70 content, or HSP90/eNOS association, 24 h after heat shock at 42°C. We also observed a 7.7 ± 1.5-fold increase in HSP70 protein content, but did not observe a change in eNOS or HSP90 24 h after heat shock at 45°C. eNOS activity and maximal bradykinin-stimulated NO release was significantly increased 24 h after heat shock at 42°C. Heat shock in rats (core temperature: 42°C, 15 min) resulted in a significant increase in aortic eNOS, HSP90, and HSP70 protein content. The aorta from heat-shocked rats exhibited a decreased maximal contractile response to phenylephrine, which was abolished by preincubation with NG-nitro-l-arginine. We conclude that prior heat shock is a physical stimulus of increased eNOS expression and is associated with an increase in eNOS activity, agonist-stimulated NO release, and a decreased vasoconstrictor response.
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Magness, Ronald R., Jeremy A. Sullivan, Yun Li, Terrance M. Phernetton, and Ian M. Bird. "Endothelial vasodilator production by uterine and systemic arteries. VI. Ovarian and pregnancy effects on eNOS and NOx." American Journal of Physiology-Heart and Circulatory Physiology 280, no. 4 (April 1, 2001): H1692—H1698. http://dx.doi.org/10.1152/ajpheart.2001.280.4.h1692.
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Normal pregnancy and the follicular phase of the ovarian cycle are both estrogen-dominated physiological states that are characterized by elevations in uterine blood flow and endothelial nitric oxide synthase (eNOS) protein expression in the uterine artery (UA) endothelium. It is unknown if elevations in mRNA level account for the changes in protein or eNOS activity. We tested the hypothesis that pregnancy and the follicular phase are associated with increases in eNOS mRNA and the consequent elevated expression of eNOS protein results in increased circulating nitric oxide (NO) levels. UA were obtained from pregnant (PREG; n = 8; 110–130 days gestation; term = 145 ± 3 days), nonpregnant luteal (LUT; n = 6), nonpregnant follicular (FOL; n= 6), and nonpregnant ovariectomized (OVEX; n = 6) sheep. Circulating NO levels were analyzed as total NO2-NO3 (NOx). Western analysis performed on UA endothelial-isolated proteins demonstrated that eNOS protein levels were OVEX = LUT ≤ FOL < PREG ( P < 0.05), whereas eNOS mRNA expression (RT-PCR) in UA endothelial cells obtained by limited collagenase digestion was OVEX < LUT < FOL < PREG ( P < 0.05). Pregnancy dramatically elevated eNOS protein (4.1- to 6.9-fold) and mRNA (2.4- to 6.9-fold) over LUT controls ( P < 0.01). Circulating NOx levels were not altered by ovariectomy or the ovarian cycle but were elevated from 4.4 ± 1.1 μM in LUT to 12 ± 4, 22 ± 3, and 41 ± 3 μM at 110, 120, and 130 days gestation ( P < 0.01). Systemic NOxlevels in singleton (12.5 ± 1.6 μM) were less ( P < 0.01) than in multiple (twin 27.6 ± 6.5 μM; triplet = 46 ± 10 μM) pregnancies. Therefore, the follicular phase and, to a much greater extent, pregnancy are associated with elevations in UA endothelium-derived eNOS expression, although significant increases in systemic NOx levels were only observed in the PREG group (multiple > singleton). Thus, although UA endothelial increases in eNOS protein and mRNA levels are associated with high estrogen states, increases in local UA NO production may require additional eNOS protein activation to play its important role in the maintenance of uterine blood flow in pregnancy.
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König, Peter, Jürgen Dedio, Stefanie Oess, Tamara Papadakis, Axel Fischer, Werner Müller-Esterl, and Wolfgang Kummer. "NOSIP and Its Interacting Protein, eNOS, in the Rat Trachea and Lung." Journal of Histochemistry & Cytochemistry 53, no. 2 (February 2005): 155–64. http://dx.doi.org/10.1369/jhc.4a6453.2005.
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Endothelial nitric oxide synthase (eNOS), the major nitric oxide (NO)-generating enzyme of the vasculature, is regulated through multiple interactions with proteins, including caveolin-1, Hsp90, Ca2+-calmodulin, and the recently discovered eNOS-interacting protein, NOSIP. Previous studies indicate that NOSIP may contribute to the intricate regulation of eNOS activity and availability. Because eNOS has been shown to be abundantly expressed in the airways, we determined the expression and cellular localization of NOSIP in rat trachea and lung by RT-PCR and immunohistochemistry and examined the interaction of NOSIP with eNOS in lung by coimmunoprecipitation. In tracheal epithelium and lung, NOSIP mRNA expression was prevalent, as shown by RT-PCR, and the corresponding protein interacted with eNOS, as demonstrated by coimmunoprecipitation. Using immunohistochemistry, we found both NOSIP and eNOS immunoreactivity in ciliated epithelial cells of trachea and bronchi, while Clara cells showed immunoreactivity for NOSIP only. NOSIP and eNOS were present in vascular and bronchial smooth muscle cells of large arteries and airways, whereas endothelial cells, as well as bronchiolar and arteriolar smooth muscle cells, exclusively stained for NOSIP. Our results point to functional role(s) of NOSIP in the control of airway and vascular diameter, mucosal secretion, NO synthesis in ciliated epithelium, and, therefore, of mucociliary and bronchial function.
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Xia, Ning, Larissa Bollinger, Katja Steinkamp-Fenske, Ulrich Förstermann, and Huige Li. "Prunella vulgaris L. Upregulates eNOS Expression in Human Endothelial Cells." American Journal of Chinese Medicine 38, no. 03 (January 2010): 599–611. http://dx.doi.org/10.1142/s0192415x10008081.
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The purported effects of "circulation-improving" herbs used in traditional Chinese medicine (TCM) show striking similarities with the vascular actions of nitric oxide (NO) produced by the endothelial NO synthase (eNOS). We have previously reported that Salviae miltiorrhizae radix and Zizyphi spinosae semen upregulate eNOS expression. In the present study, we studied the effect on eNOS gene expression of 15 Chinese herbs with potential effects on the vasculature, and identified Prunella vulgaris L. (PVL) (flowering spike) as a potent eNOS-upregulating agent. In EA.hy 926 cells, a cell line derived from human umbilical vein endothelial cells (HUVEC), an aqueous extract of PVL increased eNOS promoter activity, eNOS mRNA and protein expressions, as well as NO production in concentration- and time-dependent manners. We have previously shown that ursolic acid (a constituent of Salviae miltiorrhizae radix), betulinic acid (a compound present in Zizyphi spinosae semen), luteolin and cynaroside (ingredients of artichoke, Cynara scolymus L.) are capable of enhancing eNOS gene expression. These compounds are also present in significant quantities in PVL. Thus, PVL contains active principles that stimulate human eNOS gene expression, and such compounds may have therapeutic potential against cardiovascular diseases.
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Liu, Bingyang, Lirun Kuang, and Jingang Liu. "Bariatric surgery relieves type 2 diabetes and modulates inflammatory factors and coronary endothelium eNOS/iNOS expression in db/db mice." Canadian Journal of Physiology and Pharmacology 92, no. 1 (January 2014): 70–77. http://dx.doi.org/10.1139/cjpp-2013-0034.
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Overexpression of endothelial nitric oxide synthetase (eNOS)/inducible nitric oxide synthase (iNOS) and inhibition of inflammatory factors can improve vascular function. We hypothesized that bariatric (gastric bypass) surgery could inhibit inflammatory factors and improve the eNOS/iNOS expression of coronary arterioles in the db/db mice. The animals were randomly allocated to the following groups: sham-operated lean mice, lean mice that underwent surgery, sham-operated db/db mice, and db/db mice that underwent surgery (5, 10, 20, and 30 days post-operation). The plasma levels of adiponectin, ghrelin, and IL-6, as well as the protein expression of eNOS/iNOS in coronary arterioles were measured with Western blot. Bariatric surgery decreased body mass and blood glucose levels in db/db mice. Ghrelin receptor and GHS-R1a expression in the hypothalamus were increased in db/db mice, but surgery attenuated GHS-R1a expression. Bariatric surgery elevated plasma concentration and protein expression of adiponectin and ghrelin, and attenuated plasma concentration and protein expression of IL-6. Coronary protein expression of eNOS and SOD2 was lower in the sham-operated db/db mice, and bariatric surgery increased eNOS and SOD2 expression. Gastric bypass surgery upregulates ghrelin and adiponectin expression, and decreases IL-6 expression, which might induce up-regulation of eNOS and SOD2, and down-regulation of iNOS. These interactions could counteract the endothelium dysfunction in type 2 diabetes mellitus.
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Zhang, Ming, Chun-Mei Wang, Jing Li, Zhao-Jie Meng, Sheng-Nan Wei, Ji Li, Richard Bucala, Yu-Lin Li, and Li Chen. "Berberine Protects against Palmitate-Induced Endothelial Dysfunction: Involvements of Upregulation of AMPK and eNOS and Downregulation of NOX4." Mediators of Inflammation 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/260464.
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Endothelial dysfunction is a critical factor during the initiation of cardiovascular complications in diabetes. Berberine can ameliorate endothelial dysfunction induced by diabetes. However, the underlying mechanisms remain unclear. The aim of this study was to investigate the protective effect and mechanism of berberine on palmitate-induced endothelial dysfunction in human umbilical vein endothelial cells (HUVECs). The cell viability of HUVECs was determined by MTT assays. Nitric oxide (NO) level and production of reactive oxygen species (ROS) were determined in supernatants or in the cultured HUVECs. The mRNA level of endothelial nitric oxide synthase (eNOS) was measured by RT-PCR, and the protein levels of eNOS, p-eNOS, Akt, p-Akt, AMPK, p-AMPK, and NADPH oxidase (NOX4) were analyzed. The results demonstrated that berberine significantly elevated NO levels and reduced the production of ROS. The expressions of eNOS were significantly increased, while NOX4 protein expression was decreased in berberine-treated HUVECs. Moreover, berberine upregulated the protein expression of AMPK and p-AMPK in palmitate-treated HUVECs, but had no effect on the levels of Akt. Therefore, berberine ameliorates palmitate-induced endothelial dysfunction by upregulating eNOS expression and downregulating expression of NOX4. This regulatory effect of berberine may be related to the activation of AMPK.
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Reber, Kristina M., Baogen Y. Su, K. Reed Clark, Dana L. Pohlman, Charles E. Miller, and Philip T. Nowicki. "Developmental expression of eNOS in postnatal swine mesenteric artery." American Journal of Physiology-Gastrointestinal and Liver Physiology 283, no. 6 (December 1, 2002): G1328—G1335. http://dx.doi.org/10.1152/ajpgi.00067.2002.
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Developmental changes in the expression of endothelial nitric oxide synthase (eNOS) within the mesenteric artery of swine were studied in fetal (110 days postconception/117 days total gestation) and on postnatal days 1, 3, 10, and 30. Subjects in the 1-day-old group were subdivided into fed and nonfed. Transcription of eNOS was determined by real-time PCR, protein expression was evaluated by Western blotting, and hemodynamic and oxygenation parameters were measured within in situ gut loops before and after the administration of N G-monomethyl-l-arginine (l-NMMA). The abundance of eNOS mRNA remained steady throughout all ages. In contrast, expression of eNOS protein was twofold greater in the 1-day-old fed subjects compared with fetal or 1-day-old nonfed subjects. eNOS protein expression remained elevated on day 3, increased on day 10, and then declined to a level similar to the day 1 nonfed group by postnatal day 30. Intestinal vascular resistance was 31% lower in the day 1 fed group when compared to the day 1 nonfed group; resistance continued to decline through day 10 but then significantly increased on day 30. We conclude that the expression of eNOS changes within the mesenteric artery during early postnatal development at a posttranscriptional level.
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Le Cras, T. D., C. Xue, A. Rengasamy, and R. A. Johns. "Chronic hypoxia upregulates endothelial and inducible NO synthase gene and protein expression in rat lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 270, no. 1 (January 1, 1996): L164—L170. http://dx.doi.org/10.1152/ajplung.1996.270.1.l164.
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The effect of chronic hypoxia-induced pulmonary hypertension on nitric oxide synthase (NOS) in the lung is controversial. To clarify the regulation of endothelial and inducible NOS (eNOS and iNOS) expression in the chronically hypoxic lung, Northern and Western blot analyses were performed on mRNA and total protein from lungs of rats exposed to 3 wk of hypoxia (10% O2, normobaric) or normoxia. Expression of the mRNA and protein for eNOS was significantly increased (1.6-fold and 2.1-fold, respectively) by hypoxia. Immunohistochemistry with an isoform-specific antibody demonstrated de novo expression of eNOS in the endothelium of resistance vessels in the pulmonary vasculature of the hypoxic rats. eNOS was detected in the endothelium of large vessels in both normoxic and hypoxic rat lungs. The level of mRNA and protein for iNOS was also found to be significantly increased (1.9-fold and 1.4-fold, respectively). In addition to the 4.4-kilobase (kb) iNOS mRNA species, a novel 4.0-kb species was also induced by hypoxia. We conclude that expression of eNOS and iNOS was increased in the lungs of rats subjected to chronic hypoxia, and that there was de novo expression of eNOS protein in the microvascular endothelium.
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Davis, Michael E., Hua Cai, Louise McCann, Tohru Fukai, and David G. Harrison. "Role of c-Src in regulation of endothelial nitric oxide synthase expression during exercise training." American Journal of Physiology-Heart and Circulatory Physiology 284, no. 4 (April 1, 2003): H1449—H1453. http://dx.doi.org/10.1152/ajpheart.00918.2002.
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We have shown that c-Src plays a role in shear stress stimulation of endothelial nitric oxide synthase (eNOS) expression in cultured cells. To examine the role of c-Src in vivo, we exercised C57Blk/6 and c-Src heterozygous (c-Src+/−) mice on a treadmill for 3 wk. Western analysis demonstrated that c-Src+/− mice express less than one-half the normal amount of c-Src. Exercise increased heart rate and blood pressure to identical levels in both strains as determined using radiotelemetry. Exercise training increased eNOS protein >2-fold in the aorta and 1.7-fold in the heart in C57Blk/6 mice but had no effect on eNOS protein levels in c-Src+/− mice. In contrast to exercise, treatment of mice with mevastatin, which stimulates expression of eNOS posttranscriptionally, increased eNOS protein in both strains. Training also increased aortic extracellular superoxide dismutase protein expression, which is regulated by nitric oxide, in C57Blk/6 mice but not in c-Src+/−mice. These data indicate that c-Src has an important role in modulating vascular adaptations to exercise training, in particular increasing eNOS and extracellular superoxide dismutase protein expression.
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Ming, Xiu-Fen, Hema Viswambharan, Christine Barandier, Jean Ruffieux, Kozo Kaibuchi, Sandro Rusconi, and Zhihong Yang. "Rho GTPase/Rho Kinase Negatively Regulates Endothelial Nitric Oxide Synthase Phosphorylation through the Inhibition of Protein Kinase B/Akt in Human Endothelial Cells." Molecular and Cellular Biology 22, no. 24 (December 15, 2002): 8467–77. http://dx.doi.org/10.1128/mcb.22.24.8467-8477.2002.
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ABSTRACT Endothelial nitric oxide synthase (eNOS) is an important regulator of cardiovascular homeostasis by production of nitric oxide (NO) from vascular endothelial cells. It can be activated by protein kinase B (PKB)/Akt via phosphorylation at Ser-1177. We are interested in the role of Rho GTPase/Rho kinase (ROCK) pathway in regulation of eNOS expression and activation. Using adenovirus-mediated gene transfer in human umbilical vein endothelial cells (HUVECs), we show here that both active RhoA and ROCK not only downregulate eNOS gene expression as reported previously but also inhibit eNOS phosphorylation at Ser-1177 and cellular NO production with concomitant suppression of PKB activation. Moreover, coexpression of a constitutive active form of PKB restores the phosphorylation but not gene expression of eNOS in the presence of active RhoA. Furthermore, we show that thrombin inhibits eNOS phosphorylation, as well as expression via Rho/ROCK pathway. Expression of the active PKB reverses eNOS phosphorylation but has no effect on downregulation of eNOS expression induced by thrombin. Taken together, these data demonstrate that Rho/ROCK pathway negatively regulates eNOS phosphorylation through inhibition of PKB, whereas it downregulates eNOS expression independent of PKB.
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Arriero, Maria M., Angel Celdran, Petra Jimenez, Antonio García–Mendez, Juan C. De La Pinta, Felix Manzarbeitia, Luis Muñoz–Alameda, et al. "Aspirin Protected the Nitric Oxide/Cyclic Gmp Generating System in Human Peritoneum." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 21, no. 3_suppl (December 2001): 48–53. http://dx.doi.org/10.1177/089686080102103s08.
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♦ Objective Changes in the expression of endothelial nitric oxide synthase (eNOS) in the peritoneum could be involved in the peritoneal dysfunction associated with peritoneal inflammation. The aim of the present study was to analyze the effect of Escherichia coli lipopolysaccharide (LPS) on eNOS expression in samples of human peritoneum. The effect of aspirin, a drug with anti-inflammatory properties, was also determined. ♦ Results The eNOS protein expressed in human peritoneal tissue was reduced by LPS (10 μg/mL) in a time-dependent manner. The eNOS was expressed mainly in capillary endothelial cells and mesothelial cells. Anti-inflammatory doses of aspirin (1 – 10 mmol/L) restored eNOS expression in LPS-stimulated human peritoneal tissue samples. The main intracellular receptor of NO, soluble guanylate cyclase (sGC), was also downregulated by LPS. This effect was prevented by aspirin (5 mmol/L). ♦ Conclusion Protein expression of the eNOS–sGC system in the peritoneal tissue was downregulated by LPS. High doses of aspirin protected both eNOS protein expression and sGC in human peritoneum. These findings suggest a new mechanism of action of aspirin that could be involved in the prevention of peritoneal dysfunction during inflammation.
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Woodman, Christopher R., William G. Schrage, James W. E. Rush, Chester A. Ray, Elmer M. Price, Eileen M. Hasser, and M. Harold Laughlin. "Hindlimb unweighting decreases endothelium-dependent dilation and eNOS expression in soleus not gastrocnemius." Journal of Applied Physiology 91, no. 3 (September 1, 2001): 1091–98. http://dx.doi.org/10.1152/jappl.2001.91.3.1091.
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We tested the hypothesis that hindlimb unweighting (HLU) decreases endothelium-dependent vasodilation and expression of endothelial nitric oxide synthase (eNOS) and superoxide dismutase-1 (SOD-1) in arteries of skeletal muscle with reduced blood flow during HLU. Sprague-Dawley rats (300–350 g) were exposed to HLU ( n = 15) or control ( n = 15) conditions for 14 days. ACh-induced dilation was assessed in muscle with reduced [soleus (Sol)] or unchanged [gastrocnemius (Gast)] blood flow during HLU. eNOS and SOD-1 expression were measured in feed arteries (FA) and in first-order (1A), second-order (2A), and third-order (3A) arterioles. Dilation to infusion of ACh in vivo was blunted in Sol but not Gast. In arteries of Sol muscle, HLU decreased eNOS mRNA and protein content. eNOS mRNA content was significantly less in Sol FA (35%), 1A arterioles (25%) and 2A arterioles (18%). eNOS protein content was less in Sol FA (64%) and 1A arterioles (65%) from HLU rats. In arteries of Gast, HLU did not decrease eNOS mRNA or protein. SOD-1 mRNA expression was less in Sol 2A arterioles (31%) and 3A arterioles (29%) of HLU rats. SOD-1 protein content was less in Sol FA (67%) but not arterioles. SOD-1 mRNA and protein content were not decreased in arteries from Gast. These data indicate that HLU decreases endothelium-dependent vasodilation, eNOS expression, and SOD-1 expression primarily in arteries of Sol muscle where blood flow is reduced during HLU.
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Zheng, Jing, Ian M. Bird, Amy N. Melsaether, and Ronald R. Magness. "Activation of the Mitogen-Activated Protein Kinase Cascade Is Necessary But Not Sufficient for Basic Fibroblast Growth Factor- and Epidermal Growth Factor-Stimulated Expression of Endothelial Nitric Oxide Synthase in Ovine Fetoplacental Artery Endothelial Cells*." Endocrinology 140, no. 3 (March 1, 1999): 1399–407. http://dx.doi.org/10.1210/endo.140.3.6542.
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Abstract Basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) may play important roles in the placental vasculature, not only by controlling cell growth and differentiation, but also by mediating production of local vasodilators such as nitric oxide. As the mitogen-activated protein kinase (MAPK) signal cascade has been widely associated with cell growth in response to growth factors, herein we investigate whether bFGF, EGF, and VEGF also stimulate expression of endothelial nitric oxide synthase (eNOS) via activation of the MAPK cascade in ovine fetoplacental artery endothelial cells. The presence of the receptors for all three growth factors was confirmed by both immunocytochemistry and a functional cell proliferation assay. All three growth factors at 10 ng/ml rapidly (<10 min) activated MAPK. This activation was inhibited by PD 98059, a specific MAPK kinase inhibitor. bFGF and EGF, but not VEGF, dose- and time-dependently increased eNOS protein levels. Maximal stimulatory effects of bFGF and EGF on eNOS protein expression were observed at 10 ng/ml for 24 h of treatment and were associated with elevated eNOS messenger RNA. PD 98059 also significantly inhibited bFGF- and EGF-induced increases in eNOS protein expression. Because treatment with all three growth factors resulted in activation of the MAPK cascade, while bFGF and EGF, but not VEGF, increased eNOS expression, we conclude that activation of the MAPK cascade is necessary, but not sufficient, for bFGF- and EGF-induced increases in eNOS protein expression in ovine fetoplacental artery endothelial cells. Thus, additional signaling pathways are implicated in the different controls of eNOS expression and mitogenesis by growth factors.
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Galan, Henry L., Timothy R. H. Regnault, Timothy D. Le Cras, R. Weslie Tyson, Russell V. Anthony, Randall B. Wilkening, and Steven H. Abman. "Cotyledon and binucleate cell nitric oxide synthase expression in an ovine model of fetal growth restriction." Journal of Applied Physiology 90, no. 6 (June 1, 2001): 2420–26. http://dx.doi.org/10.1152/jappl.2001.90.6.2420.
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Heat exposure early in ovine pregnancy results in placental insufficiency and intrauterine growth restriction (PI-IUGR). We hypothesized that heat exposure in this model disrupts placental structure and reduces placental endothelial nitric oxide synthase (eNOS) protein expression. We measured eNOS protein content and performed immunohistochemistry for eNOS in placentas from thermoneutral (TN) and hyperthermic (HT) animals killed at midgestation (90 days). Placental histomorphometry was compared between groups. Compared with the TN controls, the HT group showed reduced delivery weights (457 ± 49 vs. 631 ± 21 g; P < 0.05) and a trend for reduced placentome weights (288 ± 61 vs. 554 ± 122 g; P = 0.09). Cotyledon eNOS protein content was reduced by 50% in the HT group ( P < 0.03). eNOS localized similarly to the vascular endothelium and binucleated cells (BNCs) within the trophoblast of both experimental groups. HT cotyledons showed a reduction in the ratio of fetal to maternal stromal tissue (1.36 ± 0.36 vs. 3.59 ± 1.2; P≤ 0.03). We conclude that eNOS protein expression is reduced in this model of PI-IUGR and that eNOS localizes to both vascular endothelium and the BNC. We speculate that disruption of normal vascular development and BNC eNOS production and function leads to abnormal placental vascular tone and blood flow in this model of PI-IUGR.
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Chicoine, Louis G., Jose W. Avitia, Cody Deen, Leif D. Nelin, Scott Earley, and Benjimen R. Walker. "Developmental differences in pulmonary eNOS expression in response to chronic hypoxia in the rat." Journal of Applied Physiology 93, no. 1 (July 1, 2002): 311–18. http://dx.doi.org/10.1152/japplphysiol.01083.2001.
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Chronic hypoxia (CH) increases pulmonary endothelial nitric oxide synthase (eNOS) protein levels in adult rats but decreases eNOS protein levels in neonatal pigs. We hypothesized that this differing response to CH is due to developmental rather than species differences. Adult and neonatal rats were placed in either hypobaric hypoxia or normoxia for 2 wk. At that time, body weight, hematocrit, plasma nitrite/nitrate (NOx−), and right ventricular and total ventricular heart weights were measured. Percent pulmonary arterial wall area of 20–50 and 51–100 μm arteries were also determined. Total lung protein extracts were assayed for eNOS levels by using immunoblot analysis. Compared with their respective normoxic controls, both adult and neonatal hypoxic groups demonstrated significantly decreased body weight, elevated hematocrit, and elevated right ventricular-to-total ventricular weight ratios. Both adult and neonatal hypoxic groups also demonstrated significantly larger percent pulmonary arterial wall area compared with their respective normoxic controls. Hypoxic adult pulmonary eNOS protein and plasma NOx− were significantly greater than levels found in normoxic adults. In contrast, hypoxic neonatal pulmonary eNOS protein and plasma NOx− were significantly less compared with normoxic neonates. We conclude that there is a developmental difference in eNOS expression and nitric oxide production in response to CH.
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You, Yuehua, Wanying Tan, Yongzheng Guo, Minghao Luo, Fei-fei Shang, Yong Xia, and Suxin Luo. "Progesterone promotes endothelial nitric oxide synthase expression through enhancing nuclear progesterone receptor-SP-1 formation." American Journal of Physiology-Heart and Circulatory Physiology 319, no. 2 (August 1, 2020): H341—H348. http://dx.doi.org/10.1152/ajpheart.00206.2020.
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Progesterone directly upregulated endothelial nitric oxide synthase (eNOS) expression in human endothelial cells. Progesterone augmented eNOS promoter activity through a progesterone receptor A- and specificity protein-1-dependent manner. Antagonism of the progesterone receptor reduced eNOS expression and impaired vasodilation in rats.
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Ou, Zhi-Jun, Wei Wei, Da-De Huang, Wei Luo, Dan Luo, Zhi-Ping Wang, Xi Zhang, and Jing-Song Ou. "l-Arginine restores endothelial nitric oxide synthase-coupled activity and attenuates monocrotaline-induced pulmonary artery hypertension in rats." American Journal of Physiology-Endocrinology and Metabolism 298, no. 6 (June 2010): E1131—E1139. http://dx.doi.org/10.1152/ajpendo.00107.2010.
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l-Arginine can attenuate pulmonary hypertension (PH) by a mechanism that are not fully understood. This study investigated the molecule mechanism of l-arginine attenuating PH. Sprague Dawley rats were treated with monocrotaline (MCT) with or without l-arginine for 3 or 5 wk. Right ventricular systolic pressure (RVSP), right heart hypertrophy, survival rate, pulmonary artery wall thickness, nitric oxide (NO) concentration, and superoxide anion (O2·−) generation in the lung were measured. Expressions of endothelial nitric oxide synthase (eNOS) and heat shock protein 90 (HSP90), phosphorylation of eNOS at Ser1177, and the association of eNOS and HSP90 in the lung were determined by Western blot and immunoprecipitation experiments. MCT increased RVSP, right heart hypertrophy, mortality, pulmonary artery wall thickness, and O2·− generation and decreased eNOS and HSP90 expression and association, phosphorylation of eNOS at Ser1177, and NO production. l-Arginine decreased RVSP, right heart hypertrophy, mortality, O2·− generation, and pulmonary artery wall thickness and increased NO production. l-Arginine increased eNOS expression, phosphorylation of eNOS at Ser1177, and association of eNOS and HSP90 without significantly altering HSP90 expression. l-Arginine may act through three pathways, providing a substrate for NO generation, preserving eNOS expression/phosphorylation, and maintaining the association of eNOS and HSP90, which allows restoration of eNOS activity and coupling activity, to maintain the balance between NO and O2·− and delay the development of PH.
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Takahashi, Satoru, and Yukiko Nakashima. "Repeated and long-term treatment with physiological concentrations of resveratrol promotes NO production in vascular endothelial cells." British Journal of Nutrition 107, no. 6 (July 27, 2011): 774–80. http://dx.doi.org/10.1017/s0007114511003588.
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In the present study, we examined the effect of repeated and long-term treatment with resveratrol on NO production in endothelial cells as a model of routine wine consumption. Repeated treatment with resveratrol for 5 d resulted in an increase in endothelial NO synthase (eNOS) protein content and NO production in human umbilical vein endothelial cell (HUVEC) in a concentration-dependent manner. A significant increase in functional eNOS protein content was observed with resveratrol, even at 50 nm. In contrast, eNOS phosphorylation was not stimulated and inducible NO synthase (iNOS) was not detected after resveratrol treatment. Both eNOS protein and mRNA expression were promoted by 50 nm-resveratrol in a time-dependent manner. Increased eNOS mRNA expression in response to resveratrol was not decreased by an oestrogen receptor (ER) antagonist ICI182780, a PPARα inhibitor MK886 or a sirtuin inhibitor Salermide. However, a combination of ICI182780 and MK886 significantly inhibited resveratrol-induced eNOS mRNA expression. Salermide had no effect even in the presence of ICI182780 or MK886. These results demonstrate that resveratrol within the physiological range increases eNOS mRNA and protein expression through ER and PPARα activation, thereby promoting NO production in endothelial cells. eNOS induction might result from the accumulative effect of nanomolar concentrations of resveratrol. The present study results can account in part for the observation that cardiovascular benefits of red wine are experienced with routine consumption, but not with acute consumption.
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Haider, Dominik G., Robert A. Bucek, Aura G. Giurgea, Gerald Maurer, Helmut Glogar, Erich Minar, Michael Wolzt, Mohammad R. Mehrabi, and Mehrdad Baghestanian. "PGE1analog alprostadil induces VEGF and eNOS expression in endothelial cells." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 5 (November 2005): H2066—H2072. http://dx.doi.org/10.1152/ajpheart.00147.2005.
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Endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor 1-α (HIF-1α) are important regulators of endothelial function, which plays a role in the pathophysiology of heart failure (HF). PGE1analog treatment in patients with HF elicits beneficial hemodynamic effects, but the precise mechanisms have not been investigated. We have investigated the effects of the PGE1analog alprostadil on eNOS, VEGF, and HIF-1α expression in human umbilical vein endothelial cells (HUVEC) using RT-PCR and immunoblotting under normoxic and hypoxic conditions. In addition, we studied protein expression by immunohistochemical staining in explanted hearts from patients with end-stage HF, treated or untreated with systemic alprostadil. Alprostadil causes an upregulation of eNOS and VEGF protein and mRNA expression in HUVEC and decreases HIF-1α. Hypoxia potently increased eNOS, VEGF, and HIF-1α synthesis. The alprostadil-induced upregulation of eNOS and VEGF was prevented by inhibition of MAPKs with PD-98056 or U-0126. Consistently, the expression of eNOS and VEGF was increased, and HIF-1α was reduced in failing hearts treated with alprostadil. The potent effects of alprostadil on endothelial VEGF and eNOS synthesis may be useful for patients with HF where endothelial dysfunction is involved in the disease process.
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Subotički, Tijana, Olivera Mitrović Ajtić, Emilija Živković, Miloš Diklić, Dragoslava Đikić, Milica Tošić, Bojana Beleslin-Čokić, et al. "VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms." International Journal of Molecular Sciences 22, no. 13 (June 22, 2021): 6671. http://dx.doi.org/10.3390/ijms22136671.
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Background: Chronic inflammation has been recognized in neoplastic disorders, including myeloproliferative neoplasm (MPN), as an important regulator of angiogenesis. Aims: We investigated the influence of vascular endothelial growth factor (VEGF) and pro-inflammatory interleukin-6 (IL-6) on the expression of angiogenic factors, as well as inflammation-related signaling in mononuclear cells (MNC) of patients with MPN and JAK2V617F positive human erythroleukemic (HEL) cells. Results: We found that IL-6 did not change the expression of angiogenic factors in the MNC of patients with MPN and HEL cells. However, IL-6 and the JAK1/2 inhibitor Ruxolitinib significantly increased angiogenic factors—endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor-1 alpha (HIF-1α)—in patients with polycythemia vera (PV). Furthermore, VEGF significantly increased the expression of HIF-1α and eNOS genes, the latter inversely regulated by PI3K and mTOR signaling in the MNC of primary myelofibrosis (PMF). VEGF and inhibitors of inflammatory JAK1/2, PI3K, and mTOR signaling reduced the eNOS protein expression in HEL cells. VEGF also decreased the expression of eNOS and HIF-1α proteins in the MNC of PMF. In contrast, VEGF increased eNOS and HIF-1α protein expression in the MNC of patients with PV, which was mediated by the inflammatory signaling. VEGF increased the level of IL-6 immunopositive MNC of MPN. In summary, VEGF conversely regulated gene and protein expression of angiogenic factors in the MNC of PMF, while VEGF increased angiogenic factor expression in PV mediated by the inflammation-related signaling. Conclusion: The angiogenic VEGF induction of IL-6 supports chronic inflammation that, through positive feedback, further promotes angiogenesis with concomitant JAK1/2 inhibition.
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Rupnow, Heidi L., Terrance M. Phernetton, Cynthia E. Shaw, Mary L. Modrick, Ian M. Bird, and Ronald R. Magness. "Endothelial vasodilator production by uterine and systemic arteries. VII. Estrogen and progesterone effects on eNOS." American Journal of Physiology-Heart and Circulatory Physiology 280, no. 4 (April 1, 2001): H1699—H1705. http://dx.doi.org/10.1152/ajpheart.2001.280.4.h1699.
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Uterine blood flow (UBF) and uterine artery endothelial nitric oxide synthase (eNOS) expression are greatest during the follicular vs. luteal phase. 17β-Estradiol (E2β) increases UBF and elevates eNOS in ovine uterine but not systemic arteries; progesterone (P4) effects on E2β changes of eNOS remain unclear. Nonpregnant ovariectomized sheep received either vehicle ( n = 10), P4 (0.9 g Controlled Internal Drug Release vaginal implants; n = 13), E2β (5 μg/kg bolus + 6 μg · kg−1 · day−1; n = 10), or P4 + E2β ( n = 12). Reproductive (uterine/mammary) and nonreproductive (omental/renal) artery endothelial proteins were procured on day 10, and eNOS was measured by Western analysis. P4 and E2β alone and in combination increased ( P < 0.05) eNOS expression in uterine artery endothelium (vehicle = 100 ± 16%, P4 = 251 ± 59%, E2β = 566 ± 147%, P4 + E2β = 772 ± 211% of vehicle). Neither omental, renal, nor mammary artery eNOS was altered, demonstrating the local nature of steroid-induced maintenance of uterine arterial eNOS. In the myometrial microvasculature, eNOS was increased slightly ( P = 0.06) with E2β and significantly with P4 + E2β. Systemic NOx was increased with P4 and P4 + E2β, but not E2β, suggesting differential regulation of eNOS expression and activity, since P4 increased eNOS in uterine artery endothelium while E2β and the combination further increased eNOS protein.
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Wang, Xu, and Abdel A. Abdel-Rahman. "Effect of chronic ethanol administration on hepatic eNOS activity and its association with caveolin-1 and calmodulin in female rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 289, no. 3 (September 2005): G579—G585. http://dx.doi.org/10.1152/ajpgi.00282.2004.
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Although chronic and excessive alcohol consumption is associated with liver disease, the mechanism of alcoholic liver injury is still not clear. Whether reduced hepatic production of nitric oxide, which is evident in models of liver injury, is associated with alcohol-induced liver injury has not been investigated. We measured nitric oxide synthase (NOS) activity in the liver of pair-fed rats receiving liquid diet with or without alcohol [3% (vol/vol)] for 12 wk. Compared with control rats, hepatic NOS activity was significantly reduced in alcohol-treated rats along with the evidence of liver injury. Interestingly, there was no difference in the hepatic expression of endothelial NOS (eNOS) between ethanol-fed and pair-fed rats. We then tested the hypothesis that an imbalance between the binding of eNOS with inhibitory and stimulatory proteins may underlie the reduced activity of eNOS because eNOS catalytic activity is regulated partly through dynamic interactions with the inhibitory protein caveolin-1 and the stimulatory protein calmodulin. We found that hepatic caveolin-1 was markedly increased in alcohol-treated rats compared with control rats, whereas calmodulin remained unaltered. The binding of caveolin-1 and calmodulin with eNOS was increased and decreased, respectively, in alcohol-treated rats. Our results suggest that chronic alcohol intake attenuates hepatic eNOS activity by increasing the expression of the inhibitory protein caveolin-1 and enhancing its binding with eNOS.
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Tang, Yan-hua, Jue-shen Yang, Hai-yan Xiang, and Jia-jun Xu. "PI3K-Akt/eNOS in remote postconditioning induced by brief pulmonary ischemia." Clinical & Investigative Medicine 37, no. 1 (February 1, 2014): 26. http://dx.doi.org/10.25011/cim.v37i1.20866.
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Purpose: Postconditioning, a series of brief ischemia-reperfusion sequences given before an ischemic heart undergoes sustained reperfusion, has been shown to lessen ischemia/reperfusion injury. The current study establishes a rabbit model of myocardial ischemia-reperfusion and studied the effects of pulmonary remote postconditioning in this model. Methods: Serum levels of creatine kinase (CK), superoxide dismutase (SOD), and malondialdehyde (MDA), protein expression of endothelial nitric oxide synthase (eNOS), Rho kinase (ROCK- 2), and protein kinase B (Akt) in myocardial cells and the apoptosis index of myocardial cells were examined. Results: Pulmonary remote postconditioning decreased CK, significantly decreased MDA, and increased SOD. Postconditioning significantly increased eNOS protein expression. Administration of eNOS inhibitor, L-NAME, dramatically suppressed the postconditioning-induced eNOS protein expression and serum SOD level, but significantly increased MDA level. The two longer sessions of postconditioning increased Akt, although this increase was not accompanied by changes in levels of the Akt inhibitor, ROCK-2. Blocking eNOS activity with L-NAME had no visible effect on either Akt or ROCK-2. Conclusion: Our results suggest a role for Akt in remote postconditioning-induced myocardial protection, but do not support an involvement of eNOS in Akt-mediated action.
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Resta, Thomas C., Louis G. Chicoine, John L. Omdahl, and Benjimen R. Walker. "Maintained upregulation of pulmonary eNOS gene and protein expression during recovery from chronic hypoxia." American Journal of Physiology-Heart and Circulatory Physiology 276, no. 2 (February 1, 1999): H699—H708. http://dx.doi.org/10.1152/ajpheart.1999.276.2.h699.
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We previously demonstrated augmented endothelium-derived nitric oxide (EDNO)-dependent pulmonary arterial dilation and increased arterial endothelial nitric oxide synthase (eNOS) levels in chronic hypoxic (CH) and monocrotaline (nonhypoxic) models of pulmonary arterial hypertension. Therefore, we hypothesized that the long-term elevation of arterial eNOS levels associated with CH is related to pulmonary hypertension or some factor(s) associated with hypertension and not directly to hypoxia. To test this hypothesis, we examined responses to the EDNO-dependent dilator ionomycin in U-46619-constricted, isolated, saline-perfused lungs from control rats, CH (4 wk at 380 mmHg) rats, and rats previously exposed to CH but returned to normoxia for 4 days or 2 wk. Microvascular pressure was assessed by double-occlusion technique, allowing calculation of segmental resistances. In addition, vascular eNOS immunoreactivity was assessed by quantitative immunohistochemistry, and eNOS mRNA abundance was determined by RT-PCR assays. Our findings indicate that 4-day and 2-wk posthypoxic rats exhibit persistent pulmonary hypertension, likely due to maintained arterial remodeling and polycythemia associated with prior exposure to CH. Furthermore, arterial dilation to ionomycin was augmented in lungs from each experimental group compared with controls. Finally, arterial eNOS immunoreactivity and whole lung eNOS mRNA levels remained elevated in posthypoxic animals. These findings suggest that altered vascular mechanical forces or vascular remodeling contributes to enhanced EDNO-dependent arterial dilation and upregulation of arterial eNOS in various models of established pulmonary hypertension.
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Boo, Yong Chool, and Hanjoong Jo. "Flow-dependent regulation of endothelial nitric oxide synthase: role of protein kinases." American Journal of Physiology-Cell Physiology 285, no. 3 (September 2003): C499—C508. http://dx.doi.org/10.1152/ajpcell.00122.2003.
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Vascular endothelial cells are directly and continuously exposed to fluid shear stress generated by blood flow. Shear stress regulates endothelial structure and function by controlling expression of mechanosensitive genes and production of vasoactive factors such as nitric oxide (NO). Though it is well known that shear stress stimulates NO production from endothelial nitric oxide synthase (eNOS), the underlying molecular mechanisms remain unclear and controversial. Shear-induced production of NO involves Ca2+/calmodulin-independent mechanisms, including phosphorylation of eNOS at several sites and its interaction with other proteins, including caveolin and heat shock protein-90. There have been conflicting results as to which protein kinases—protein kinase A, protein kinase B (Akt), other Ser/Thr protein kinases, or tyrosine kinases—are responsible for shear-dependent eNOS regulation. The functional significance of each phosphorylation site is still unclear. We have attempted to summarize the current status of understanding in shear-dependent eNOS regulation.
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Xu, Xiongfei, Zhongzhuang Wang, Quan Li, Xiang Xiao, Qinglin Lian, Weigang Xu, Xuejun Sun, Hengyi Tao, and Runping Li. "Endothelial Nitric Oxide Synthase Expression Is Progressively Increased in Primary Cerebral Microvascular Endothelial Cells During Hyperbaric Oxygen Exposure." Oxidative Medicine and Cellular Longevity 2, no. 1 (2009): 7–13. http://dx.doi.org/10.4161/oxim.2.1.7697.
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Exposure to hyperbaric oxygen (HBO) can lead to seizures. Many studies have demonstrated that there exist a very close relationship between the alteration of cerebral blood flow (CBF) and the onset of seizures. Nitric oxide (NO) may play a key role in the change of CBF during exposure, and modulation of endothelial nitric oxide synthase (eNOS)-derived NO by HBO is responsible for early vasoconstriction, whereas late HBO-induced vasodilation depends upon a large amount of NO from both eNOS and neuronal nitric oxide synthase (nNOS). To investigate the effect of HBO on the activity and expression of eNOS in cerebral microvascular endothelial cells (CMEC) in vitro, primarily cultured CMEC from neonatal rats were exposed to oxygen at 500 kPa [5 atmosphere absolute (ATA)] for 10, 20, 30, 60 and 120 minutes (min), then eNOS activity, protein and mRNA contents in cells were detected. Our results showed that immediately after exposure, 30, 60 and 120 min HBO exposures did not alter NOS activity. When detected no matter immediately or six hours (h) after exposure, these exposures also did not alter eNOS protein and mRNA levels. However, when detected 24 h after exposure, 30, 60 and 120 min exposures upregulated eNOS protein content by 39%, 60% and 40% respectively. 10 and 20 min exposures upregulated eNOS mRNA content by about 15%, while 30, 60 and 120 min exposures upregulated it by about 20–30%. The increased eNOS protein and mRNA contents at 24 h after exposure may reflect new protein synthesis for eNOS. Our studies showed that with the exposing protocols we used, HBO did induce eNOS expression increase in CMEC. However, compared with the decrease of CBF in vivo, which occurred in a relative short time after rat was exposed to HBO above 4 ATA, the responses of eNOS in CMEC in vitro were a little slow. Thus we considered that for the vasodilation in the late period of HBO exposure before seizure, the effect of NO produced by eNOS was limited.
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Dai, Yuemeng. "Decreased eNOS Protein Expression in Involuting and Propranolol-Treated Hemangiomas." Archives of Otolaryngology–Head & Neck Surgery 138, no. 2 (February 1, 2012): 177. http://dx.doi.org/10.1001/archoto.2011.1096.
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Mohamed, Salah A., Arlo Radtke, Roza Saraei, Joern Bullerdiek, Hajar Sorani, Rolf Nimzyk, Antje Karluss, Hans H. Sievers, and Gazanfer Belge. "Locally Different Endothelial Nitric Oxide Synthase Protein Levels in Ascending Aortic Aneurysms of Bicuspid and Tricuspid Aortic Valve." Cardiology Research and Practice 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/165957.
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Aims. Dysregulated expression of the endothelial nitric oxide synthase (eNOS) is observed in aortic aneurysms associated with bicuspid aortic valve (BAV). We determined eNOS protein levels in various areas in ascending aortic aneurysms.Methods and Results. Aneurysmal specimens were collected from 19 patients, 14 with BAV and 5 with tricuspid aortic valve (TAV). ENOS protein levels were measured in the outer curve (convexity), the opposite side (concavity), the distal and above the sinotubular junction (proximal) aneurysm. Cultured aortic cells were treated with NO synthesis inhibitor L-NAME and the amounts of 35 apoptosis-related proteins were determined. In patients with BAV, eNOS levels were significantly lower in the proximal aorta than in the concavity and distal aorta. ENOS protein levels were also lower in the convexity than in the concavity. While the convexity and distal aorta showed similar eNOS protein levels in BAV and TAV patients, levels were higher in TAV proximal aorta. Inhibition of NO synthesis in aneurysmal aortic cells by L-NAME led to a cytosolic increase in the levels of mitochondrial serine protease HTRA2/Omi.Conclusion. ENOS protein levels were varied at different areas of the aneurysmal aorta. The dysregulation of nitric oxide can lead to an increase in proapoptotic HTRA2/Omi.
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Qi, Wen-Ning, Zuo-Qin Yan, Peter G. Whang, Qi Zhou, Long-En Chen, Anthony V. Seaber, Jonathan S. Stamler, and James R. Urbaniak. "Gene and protein expressions of nitric oxide synthases in ischemia-reperfused peripheral nerve of the rat." American Journal of Physiology-Cell Physiology 281, no. 3 (September 1, 2001): C849—C856. http://dx.doi.org/10.1152/ajpcell.2001.281.3.c849.
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This study examined mRNA and protein expressions of neuronal (nNOS), inducible (iNOS), and endothelial nitric oxide synthases (eNOS) in peripheral nerve after ischemia-reperfusion (I/R). Sixty-six rats were divided into the ischemia only and I/R groups. One sciatic nerve of each animal was used as the experimental side and the opposite untreated nerve as the control. mRNA levels in the nerve were quantitatively measured by competitive PCR, and protein was determined by Western blotting and immunohistochemical staining. The results showed that, after ischemia (2 h), both nNOS and eNOS protein expressions decreased. After I/R (2 h of ischemia followed by 3 h of reperfusion), expression of both nNOS and eNOS mRNA and protein decreased further. In contrast, iNOS mRNA significantly increased after ischemia and was further upregulated (14-fold) after I/R, while iNOS protein was not detected. The results reveal the dynamic expression of individual NOS isoforms during the course of I/R injury. An understanding of this modulation on a cellular and molecular level may lead to understanding the mechanisms of I/R injury and to methods of ameliorating peripheral nerve injury.
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Fleming, Ingrid, and Rudi Busse. "Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 284, no. 1 (January 1, 2003): R1—R12. http://dx.doi.org/10.1152/ajpregu.00323.2002.
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The endothelial nitric oxide synthase (eNOS), the expression of which is regulated by a range of transcriptional and posttranscriptional mechanisms, generates nitric oxide (NO) in response to a number of stimuli. The physiologically most important determinants for the continuous generation of NO and thus the regulation of local blood flow are fluid shear stress and pulsatile stretch. Although eNOS activity is coupled to changes in endothelial cell Ca2+ levels, an increase in Ca2+ alone is not sufficient to affect enzyme activity because the binding of calmodulin (CaM) and the flow of electrons from the reductase to the oxygenase domain of the enzyme is dependent on protein phosphorylation and dephosphorylation. Two amino acids seem to be particularly important in regulating eNOS activity and these are a serine residue in the reductase domain (Ser1177) and a threonine residue (Thr495) located within the CaM-binding domain. Simultaneous alterations in the phosphorylation of Ser1177 and Thr495 in response to a variety of stimuli are regulated by a number of kinases and phosphatases that continuously associate with and dissociate from the eNOS signaling complex. eNOS associated proteins, such as caveolin, heat shock protein 90, eNOS interacting protein, and possibly also motor proteins provide the scaffold for the formation of the protein complex as well as its intracellular localization.
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Welter, H., H. Bollwein, F. Weber, S. Rohr, and R. Einspanier. "Expression of endothelial and inducible nitric oxide synthases is modulated in the endometrium of cyclic and early pregnant mares." Reproduction, Fertility and Development 16, no. 7 (2004): 689. http://dx.doi.org/10.1071/rd03103.
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The expression of the endothelial and inducible nitric oxide synthases (eNOS and iNOS, respectively) was examined in the endometrium of cyclic and pregnant mares by real-time polymerase chain reaction and immunohistology. The concentration of eNOS mRNA varied throughout the oestrous cycle, with significantly higher transcripts on Day 5 of the oestrous cycle (P < 0.05), whereas iNOS transcription did not change significantly over time (P > 0.05). In early pregnant mares both eNOS and iNOS mRNA increased between Days 12 and 15 (P < 0.05). In cyclic mares, eNOS protein was detected immunocytochemically in endometrial epithelia, the basement membrane, the endothelial layer and smooth muscle cells of the vasculature. Using immunocytochemical methods, iNOS protein was undetectable in the endometrium of cyclic mares but could be demonstrated in pregnant mares. Endometrial epithelia of pregnant mares were immunopositive for both proteins with a more intense labelling for iNOS. Thus, the present study describes for the first time the modulation and spatial distribution of eNOS and iNOS expression during the oestrous cycle and early pregnancy, suggesting that ovarian steroids are differently involved in the regulation of each NOS. Localisation of eNOS protein in endometrial epithelia and various vascular components indicates that this isoform may be involved in the regulation of endometrial cyclicity. The presence and increase of both forms of NOS during early gestation suggest a role for them in the control of endometrial vascular bed and glandular activity to provide a suitable microenvironment for successful pregnancy.
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Tyler, Robert C., Masashi Muramatsu, Steven H. Abman, Thomas J. Stelzner, David M. Rodman, Kenneth D. Bloch, and Ivan F. McMurtry. "Variable expression of endothelial NO synthase in three forms of rat pulmonary hypertension." American Journal of Physiology-Lung Cellular and Molecular Physiology 276, no. 2 (February 1, 1999): L297—L303. http://dx.doi.org/10.1152/ajplung.1999.276.2.l297.
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Endothelial nitric oxide (NO) synthase (eNOS) mRNA and protein and NO production are increased in hypoxia-induced hypertensive rat lungs, but it is uncertain whether eNOS gene expression and activity are increased in other forms of rat pulmonary hypertension. To investigate these questions, we measured eNOS mRNA and protein, eNOS immunohistochemical localization, perfusate NO product levels, and NO-mediated suppression of resting vascular tone in chronically hypoxic (3–4 wk at barometric pressure of 410 mmHg), monocrotaline-treated (4 wk after 60 mg/kg), and fawn-hooded (6–9 mo old) rats. eNOS mRNA levels (Northern blot) were greater in hypoxic and monocrotaline-treated lungs (130 and 125% of control lungs, respectively; P < 0.05) but not in fawn-hooded lungs. Western blotting indicated that eNOS protein levels increased to 300 ± 46% of control levels in hypoxic lungs ( P < 0.05) but were decreased by 50 ± 5 and 60 ± 11%, respectively, in monocrotaline-treated and fawn-hooded lungs ( P < 0.05). Immunostaining showed prominent eNOS expression in small neomuscularized arterioles in all groups, whereas perfusate NO product levels increased in chronically hypoxic lungs (3.4 ± 1.4 μM; P < 0.05) but not in either monocrotaline-treated (0.7 ± 0.3 μM) or fawn-hooded (0.45 ± 0.1 μM) lungs vs. normotensive lungs (0.12 ± 0.07 μM). All hypertensive lungs had increased baseline perfusion pressure in response to nitro-l-arginine but not to the inducible NOS inhibitor aminoguanidine. These results indicate that even though NO activity suppresses resting vascular tone in pulmonary hypertension, there are differences among the groups regarding eNOS gene expression and NO production. A better understanding of eNOS gene expression and activity in these models may provide insights into the regulation of this vasodilator system in various forms of human pulmonary hypertension.
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Yu, Lan, Meihui Yin, Xueyan Yang, Meili Lu, Futian Tang, and Hongxin Wang. "Calpain inhibitor I attenuates atherosclerosis and inflammation in atherosclerotic rats through eNOS/NO/NF-κB pathway." Canadian Journal of Physiology and Pharmacology 96, no. 1 (January 2018): 60–67. http://dx.doi.org/10.1139/cjpp-2016-0652.
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We previously reported that calpain, the Ca2+-sensitive cysteine protease, gets involved in atherogenesis. This study aimed to investigate the effects of calpain inhibitor I (CAI, 5 mg/kg per day) with or without NG-nitro-l-arginine-methyl ester (l-NAME) (100 mg/kg per day), the inhibitor of nitric oxide synthase (NOS), on atherosclerosis and inflammation in a rat model induced by high-cholesterol diet (HCD). The results demonstrated HCD increased protein expression of calpain-1 but not calpain-2 in aortic tissue. In addition, CAI reduced the thickness of atherosclerotic intima compared with HCD group, which was weakened by the l-NAME combination. CAI with or without l-NAME decreased the activity of calpain in the aorta. Also, CAI decreased the expressions of vascular cell adhesion molecule-1 (VCAM-1), intracellular cell adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1) in the aorta at the levels of both mRNA and protein. Furthermore, CAI increased the activity and the protein expression of endothelial NOS (eNOS) accompanied by increased content of NO and downregulated the protein expression of nuclear factor κB (NF-κB) of the nucleus in the aorta. However, the abovementioned effects were at least partly cancelled by l-NAME except for the protein expression of eNOS. The results suggested that CAI attenuated atherosclerosis and inflammation through eNOS/NO/NF-κB pathway.
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DAI, Zen-Kong, Mian-Shin TAN, Chee-Yin CHAI, Ing-Jun CHEN, Arco Y. JENG, and Jiunn-Ren WU. "Effects of increased pulmonary flow on the expression of endothelial nitric oxide synthase and endothelin-1 in the rat." Clinical Science 103, s2002 (September 1, 2002): 289S—293S. http://dx.doi.org/10.1042/cs103s289s.
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The purpose of the study was to assess whether increased pulmonary flow and subsequent development of pulmonary vascular remodelling could alter the expression of endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) in the rat lung. Nine 42-day-old Wistar rats underwent abdominal aortocaval shunt to increase pulmonary blood flow for 12 weeks. The shunt resulted in significant medial hypertrophy of pulmonary artery without significant alterations in pulmonary or systemic blood pressure. Using competitive reverse transcription–PCR, significant increases in the preproET-1 mRNA expression and eNOS mRNA expression in the lungs of rats with abdominal aortocaval shunt were detected. Increased eNOS protein in the lung of shunt rats was also found by Western blot analysis. However, the plasma ET-1 concentration in the pulmonary artery (sham: 5±0.7pg/ml; shunt: 6±0.8pg/ml) or the lung ET-1 content (sham: 218±41ng/g protein; shunt: 224±40ng/g protein) was unchanged. There was an elevated immunohistochemical expression of eNOS, but not ET-1, in the pulmonary vascular endothelium in rats with the shunt. These results suggest that eNOS and ET-1 may be involved in remodelling prior to the development of pulmonary hypertension.
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Kim, Hae-yoong, In-chan Seol, Ho-ryong Yoo, and Yoon-sik Kim. "The Effect of Trichosanthes Kirilowii Maximowicz Extract and Trichosanthes Kirilowii Maximowicz Cheonghyeol Plus on Anti-Inflammatory Factor Expression in Human Umbilical Vein Endothelial Cells (HUVECs)." Journal of Internal Korean Medicine 43, no. 4 (September 30, 2022): 514–28. http://dx.doi.org/10.22246/jikm.2022.43.4.514.
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Objective: To examine the effects of Trichosanthes kirilowii Maximowicz extract (TE) and Trichosanthes kirilowii Maxi mowicz Cheonghyeol Plus Phellinus linteus Cheonghyeol plus (TCP) on anti-inflammatory factor expression in human umbilical vein endothelial cells (HUVECs).Methods: HUVECs were activated with TNF-α and then treated with TE and TCP. The expression levels were then measured for intracellular genes (KLF2, eNOS, MCP-1, ICAM-1, and VCAM-1), proteins (KLF2, eNOS, MCP-1, ICAM-1, VCAM-1, ERK, and JNK, p38), and extracellular biomarkers (ICAM-1, VCAM-1, and MCP-1).Results:1. TCP at concentrations of 100 μg/mL or greater significantly increased the expression of KLF2 and eNOS intracellular genes and significantly decreased the expression of ICAM-1, VCAM-1, and MCP-1 genes compared to the control group.</br>2. TCP at concentrations of 100 μg/mL or greater significantly increased the expression of KLF2, eNOS proteins compared to the control group, and significantly reduced the expression of VCAM-1, ICAM-1, MCP-1, ERK, and p38 proteins. However, JNK protein phosphorylation showed no significant change compared to the control group.</br>3. TCP at concentrations of 100 μg/mL or more significantly decreased the production of MCP-1, ICAM-1, and VCAM-1 extracellular biomarkers compared to the control group.</br>4. TE at a concentration of 100 μg/mL did not cause any significant change in the expression of intracellular genes or proteins, in the production of the extracellular biomarker MCP-1, or in the amount of JNK protein compared to the control group. Other intracellular genes, proteins, and extracellular biomarker expression showed the same trend as observed with TCP exposure.Conclusion: This study experimentally confirmed that TE and TCP could be effective in preventing or inhibiting various inflammatory vascular diseases due to their anti-inflammatory effects.
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d’Uscio, Livius V., Tongrong He, Anantha V. Santhanam, and Zvonimir S. Katusic. "Endothelium-specific amyloid precursor protein deficiency causes endothelial dysfunction in cerebral arteries." Journal of Cerebral Blood Flow & Metabolism 38, no. 10 (September 29, 2017): 1715–26. http://dx.doi.org/10.1177/0271678x17735418.
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The exact physiological function of amyloid-β precursor protein (APP) in endothelial cells is unknown. Endothelium-specific APP-deficient (eAPP−/−) mice were created to gain new insights into the role of APP in the control of vascular endothelial function. Endothelium-dependent relaxations to acetylcholine were significantly impaired in basilar arteries of global APP knockout (APP−/−) and eAPP−/− mice ( P < 0.05). In contrast, endothelium-independent relaxations to nitric oxide (NO)-donor diethylamine-NONOate were unchanged. Western blot analysis revealed that protein expression of endothelial nitric oxide synthase (eNOS) was significantly downregulated in large cerebral arteries of APP−/− mice and eAPP−/− mice as compared to respective wild-type littermates ( P < 0.05). Furthermore, basal levels of cyclic guanosine monophosphate (cGMP) were also significantly reduced in large cerebral arteries of APP-deficient mice ( P < 0.05). In contrast, protein expression of prostacyclin synthase as well as levels of cyclic adenosine monophosphate (cAMP) was not affected by genetic inactivation of APP in endothelial cells. By using siRNA to knockdown APP in cultured human brain microvascular endothelial cells we also found a significant downregulation of eNOS mRNA and protein expressions in APP-deficient endothelium ( P < 0.05). These findings indicate that under physiological conditions, expression of APP in cerebral vascular endothelium plays an important protective function by maintaining constitutive expression of eNOS .
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Di Nardo Di Maio, F., Z. Lohinai, C. D’Arcangelo, P. Esposito De Fazio, L. Speranza, M. A. De Lutiis, A. Patruno, A. Grilli, and M. Felaco. "Nitric Oxide Synthase in Healthy and Inflamed Human Dental Pulp." Journal of Dental Research 83, no. 4 (April 2004): 312–16. http://dx.doi.org/10.1177/154405910408300408.
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Nitric oxide synthase (NOS) plays a significant role in the pathogenesis of pulpitis. In this study, we hypothesized the existence of endothelial (eNOS) and inducible (iNOS) enzyme isoforms in human dental pulp. Extracted third molar pulps were divided into groups based on clinical diagnosis: healthy, hyperemic, and irreversible pulpitis. We have localized the eNOS and iNOS by immunohistochemistry and have tested their mRNA expression by RT-PCR and protein levels by Western blots. eNOS is present in the endothelial cells and odontoblasts of the healthy pulp, but an elevation of eNOS mRNA and protein levels with a concomitant dilation of vessels was characteristic under pathological conditions. Healthy pulp tissue failed to exhibit any iNOS; however, acute inflammation enhanced the mRNA and protein levels of iNOS, mainly in the leukocytes. There are differences in localization and expression between eNOS and iNOS in healthy and inflamed dental pulp.