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Journal articles on the topic 'Atherogenesis; Gene encoding'
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1
Lozhkin, A. P., T. B. Biktagirov, O. V. Gorshkiv, E. V. Timonina, G. V. Mamin, S. B. Orlinskii, N. I. Silkin, et al. "Manganese in atherogenesis: detection, origin, and role." Biomeditsinskaya Khimiya 58, no. 3 (2012): 291–99. http://dx.doi.org/10.18097/pbmc20125803291.
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The role of transition metal ions in atherogenesis is controversial; they can participate in the hydroxyl radical generation and catalyze the reactive oxygen species neutralization reaction as cofactors of antioxidant enzymes. Using EPR spectroscopy, we revealed that 70% of the samples of aorta with atherosclerotic lesions possessed superoxide dismutase activity, 100% of the samples initiated Fenton reaction and demonstrated the presence of manganese paramagnetic centers. The sodA gene encoding manganese-dependent bacterial superoxide dismutase was not found in the samples of atherosclerotic plaques by PCR using degenerate primers. The data obtained indicates the perspectives of manganese analysis as a marker element in the express diagnostics of atherosclerosis.
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Ponomarenko, Mikhail, Dmitry Rasskazov, Irina Chadaeva, Ekaterina Sharypova, Irina Drachkova, Dmitry Oshchepkov, Petr Ponomarenko, et al. "Candidate SNP Markers of Atherogenesis Significantly Shifting the Affinity of TATA-Binding Protein for Human Gene Promoters Show Stabilizing Natural Selection as a Sum of Neutral Drift Accelerating Atherogenesis and Directional Natural Selection Slowing It." International Journal of Molecular Sciences 21, no. 3 (February 5, 2020): 1045. http://dx.doi.org/10.3390/ijms21031045.
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(1) Background: The World Health Organization (WHO) regards atherosclerosis-related myocardial infarction and stroke as the main causes of death in humans. Susceptibility to atherogenesis-associated diseases is caused by single-nucleotide polymorphisms (SNPs). (2) Methods: Using our previously developed public web-service SNP_TATA_Comparator, we estimated statistical significance of the SNP-caused alterations in TATA-binding protein (TBP) binding affinity for 70 bp proximal promoter regions of the human genes clinically associated with diseases syntonic or dystonic with atherogenesis. Additionally, we did the same for several genes related to the maintenance of mitochondrial genome integrity, according to present-day active research aimed at retarding atherogenesis. (3) Results: In dbSNP, we found 1186 SNPs altering such affinity to the same extent as clinical SNP markers do (as estimated). Particularly, clinical SNP marker rs2276109 can prevent autoimmune diseases via reduced TBP affinity for the human MMP12 gene promoter and therefore macrophage elastase deficiency, which is a well-known physiological marker of accelerated atherogenesis that could be retarded nutritionally using dairy fermented by lactobacilli. (4) Conclusions: Our results uncovered SNPs near clinical SNP markers as the basis of neutral drift accelerating atherogenesis and SNPs of genes encoding proteins related to mitochondrial genome integrity and microRNA genes associated with instability of the atherosclerotic plaque as a basis of directional natural selection slowing atherogenesis. Their sum may be stabilizing the natural selection that sets the normal level of atherogenesis.
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Xu, Jing, Wenlong Li, Xunna Bao, Hu Ding, Jingzhou Chen, Weili Zhang, Kai Sun, et al. "Association of putative functional variants in the PLAU gene and the PLAUR gene with myocardial infarction." Clinical Science 119, no. 8 (July 6, 2010): 353–59. http://dx.doi.org/10.1042/cs20100151.
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uPA (urokinase-plasminogen activator) and its receptor (uPAR) have been implicated in a broad spectrum of pathophysiological processes, including fibrinolysis, proteolysis, inflammation, atherogenesis and plaque destabilization, all of which are involved in the pathogenesis of MI (myocardial infarction). We hypothesized that putative functional genetic variation in the two genes encoding uPA and uPAR (PLAU and PLAUR respectively) might influence the susceptibility to MI. We genotyped rs4065 [3′-UTR (untranslated region) *141C>T) and rs2227564 (Pro141Leu) in the PLAU gene as well as rs344781 (−516T>C) in the PLAUR gene in 633 MI patients and 1237 gender- and age-matched control subjects. Our results showed that the T allele of rs4065 was significantly associated with an increased risk of MI, with an adjusted OR (odds ratio) of 1.38 [95% CI (confidence interval), 1.07–1.78; P=0.012) under the dominant model, 1.4 (95% CI, 1.12–1.75; P=0.003) under the additive model and 2.5 (95% CI, 1.15–5.41; P=0.02) under the recessive model. The findings were then replicated in another independent case-control study including 545 MI patients and 597 control subjects. In conclusion, our results suggest that rs4065 might be a previously unknown genetic risk factor for MI in the Chinese Han population.
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Galgani, Andrea, AnaMaria Valdes, Henry A. Erlich, Calvin Mano, Suzanne Cheng, Antonio Petrone, Federica Sentinelli, Andrea Berni, Marco G. Baroni, and Raffaella Buzzetti. "Homozygosity for the Ala Allele of the PPARγ2 Pro12Ala Polymorphism Is Associated with Reduced Risk of Coronary Artery Disease." Disease Markers 29, no. 5 (2010): 259–64. http://dx.doi.org/10.1155/2010/501730.
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Several studies suggest that the peroxisome proliferator-activated receptor gamma (PPARγ) is involved in atherogenesis. The Pro12Ala polymorphism in the gene encoding PPARγ (PPARγ2 gene) influences the risk for type 2 diabetes. Two population-based studies have shown that the Ala allele is associated with reduced carotid intimal-medial thickness (IMT). However, studies focusing on acute clinical events have yielded conflicting results. Our aim was to evaluate the role of the Pro12AlaPPARγ2 polymorphism on the risk of coronary artery disease (CAD) in an Italian population with a case-controlled genetic association study in which 478 CAD patients and 218 controls were genotyped for the Pro12Ala polymorphism. CAD was diagnosed by angiography. We found that homozygotes for the Ala12 allele had a significantly reduced risk of CAD after adjusting for diabetes, sex, age, body mass index (BMI), smoking, lipids and hypertension (OR = 0.007; 95% C.I. = 0.00–0.32p< 0.011). In this casecontrol study, homozygosity for the Ala allele at codon 12 of thePPAR2 gene resulted in reduced risk of CAD. This is consistent with reports from previous studies focusing on atherosclerosis and myocardial infarction.
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Gold, Elizabeth S., Stephen A. Ramsey, Mark J. Sartain, Jyrki Selinummi, Irina Podolsky, David J. Rodriguez, Robert L. Moritz, and Alan Aderem. "ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol–induced lipid body formation." Journal of Experimental Medicine 209, no. 4 (April 2, 2012): 807–17. http://dx.doi.org/10.1084/jem.20111202.
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Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-loaded macrophages in the arterial wall. We demonstrate that macrophage lipid body formation can be induced by modified lipoproteins or by inflammatory Toll-like receptor agonists. We used an unbiased approach to study the overlap in these pathways to identify regulators that control foam cell formation and atherogenesis. An analysis method integrating epigenomic and transcriptomic datasets with a transcription factor (TF) binding site prediction algorithm suggested that the TF ATF3 may regulate macrophage foam cell formation. Indeed, we found that deletion of this TF results in increased lipid body accumulation, and that ATF3 directly regulates transcription of the gene encoding cholesterol 25-hydroxylase. We further showed that production of 25-hydroxycholesterol (25-HC) promotes macrophage foam cell formation. Finally, deletion of ATF3 in Apoe−/− mice led to in vivo increases in foam cell formation, aortic 25-HC levels, and disease progression. These results define a previously unknown role for ATF3 in controlling macrophage lipid metabolism and demonstrate that ATF3 is a key intersection point for lipid metabolic and inflammatory pathways in these cells.
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Weber, Kim S. C., Georg Draude, Wolfgang Erl, Rainer de Martin, and Christian Weber. "Monocyte Arrest and Transmigration on Inflamed Endothelium in Shear Flow Is Inhibited by Adenovirus-Mediated Gene Transfer of IκB-." Blood 93, no. 11 (June 1, 1999): 3685–93. http://dx.doi.org/10.1182/blood.v93.11.3685.
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Abstract Mobilization of nuclear factor-κB (NF-κB) activates transcription of genes encoding endothelial adhesion molecules and chemokines that contribute to monocyte infiltration critical in atherogenesis. Inhibition of NF-κB has been achieved by pharmacological and genetic approaches; however, monocyte interactions with activated endothelium in shear flow following gene transfer of the NF-κB inhibitor IκB- have not been studied. We found that overexpression of IκB- in endothelial cells using a recombinant adenovirus prevented tumor necrosis factor- (TNF-)–induced degradation of IκB- and suppressed the upregulation of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin mRNA and surface protein expression and the upregulation of transcripts for the chemokines monocyte chemoattractant protein 1 (MCP-1) and growth-related activity- (GRO-) by TNF-. This was associated with a reduction in endothelial MCP-1 secretion and GRO- immobilization. Adhesion assays under physiological shear flow conditions showed that firm arrest, spreading, and transmigration of monocytes on TNF-–activated endothelium was markedly inhibited by IκB- overexpression. Inhibition with monoclonal antibodies and peptide antagonists inferred that this was due to reduced expression of Ig integrin ligand as well as of chemokines specifically involved in these events. In contrast, rolling of monocytes was increased by IκB- transfer and was partly mediated by P-selectin; however, it appeared to be unaffected by the inhibition of E-selectin induction. Thus, our data provide novel evidence that selective modulation of NF-κB by adenoviral transfer of IκB- impairs the expression of multiple endothelial gene products required for subsequent monocyte arrest and emigration in shear flow and thus for monocyte infiltration in atherosclerotic plaques.
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Weber, Kim S. C., Georg Draude, Wolfgang Erl, Rainer de Martin, and Christian Weber. "Monocyte Arrest and Transmigration on Inflamed Endothelium in Shear Flow Is Inhibited by Adenovirus-Mediated Gene Transfer of IκB-." Blood 93, no. 11 (June 1, 1999): 3685–93. http://dx.doi.org/10.1182/blood.v93.11.3685.411k16_3685_3693.
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Mobilization of nuclear factor-κB (NF-κB) activates transcription of genes encoding endothelial adhesion molecules and chemokines that contribute to monocyte infiltration critical in atherogenesis. Inhibition of NF-κB has been achieved by pharmacological and genetic approaches; however, monocyte interactions with activated endothelium in shear flow following gene transfer of the NF-κB inhibitor IκB- have not been studied. We found that overexpression of IκB- in endothelial cells using a recombinant adenovirus prevented tumor necrosis factor- (TNF-)–induced degradation of IκB- and suppressed the upregulation of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin mRNA and surface protein expression and the upregulation of transcripts for the chemokines monocyte chemoattractant protein 1 (MCP-1) and growth-related activity- (GRO-) by TNF-. This was associated with a reduction in endothelial MCP-1 secretion and GRO- immobilization. Adhesion assays under physiological shear flow conditions showed that firm arrest, spreading, and transmigration of monocytes on TNF-–activated endothelium was markedly inhibited by IκB- overexpression. Inhibition with monoclonal antibodies and peptide antagonists inferred that this was due to reduced expression of Ig integrin ligand as well as of chemokines specifically involved in these events. In contrast, rolling of monocytes was increased by IκB- transfer and was partly mediated by P-selectin; however, it appeared to be unaffected by the inhibition of E-selectin induction. Thus, our data provide novel evidence that selective modulation of NF-κB by adenoviral transfer of IκB- impairs the expression of multiple endothelial gene products required for subsequent monocyte arrest and emigration in shear flow and thus for monocyte infiltration in atherosclerotic plaques.
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Price, Nathan L., Xinbo Zhang, Pablo Fernández-Tussy, Abhishek K. Singh, Sean A. Burnap, Noemi Rotllan, Leigh Goedeke, et al. "Loss of hepatic miR-33 improves metabolic homeostasis and liver function without altering body weight or atherosclerosis." Proceedings of the National Academy of Sciences 118, no. 5 (January 25, 2021): e2006478118. http://dx.doi.org/10.1073/pnas.2006478118.
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miR-33 is an intronic microRNA within the gene encoding the SREBP2 transcription factor. Like its host gene, miR-33 has been shown to be an important regulator of lipid metabolism. Inhibition of miR-33 has been shown to promote cholesterol efflux in macrophages by targeting the cholesterol transporter ABCA1, thus reducing atherosclerotic plaque burden. Inhibition of miR-33 has also been shown to improve high-density lipoprotein (HDL) biogenesis in the liver and increase circulating HDL-C levels in both rodents and nonhuman primates. However, evaluating the extent to which these changes in HDL metabolism contribute to atherogenesis has been hindered by the obesity and metabolic dysfunction observed in whole-body miR-33–knockout mice. To determine the impact of hepatic miR-33 deficiency on obesity, metabolic function, and atherosclerosis, we have generated a conditional knockout mouse model that lacks miR-33 only in the liver. Characterization of this model demonstrates that loss of miR-33 in the liver does not lead to increased body weight or adiposity. Hepatic miR-33 deficiency actually improves regulation of glucose homeostasis and impedes the development of fibrosis and inflammation. We further demonstrate that hepatic miR-33 deficiency increases circulating HDL-C levels and reverse cholesterol transport capacity in mice fed a chow diet, but these changes are not sufficient to reduce atherosclerotic plaque size under hyperlipidemic conditions. By elucidating the role of miR-33 in the liver and the impact of hepatic miR-33 deficiency on obesity and atherosclerosis, this work will help inform ongoing efforts to develop novel targeted therapies against cardiometabolic diseases.
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Salerno, Alessandro G., Thiago Rentz, Gabriel G. Dorighello, Ana Carolina Marques, Estela Lorza-Gil, Amarylis C. B. A. Wanschel, Audrey de Moraes, Anibal E. Vercesi, and Helena C. F. Oliveira. "Lack of mitochondrial NADP(H)-transhydrogenase expression in macrophages exacerbates atherosclerosis in hypercholesterolemic mice." Biochemical Journal 476, no. 24 (December 20, 2019): 3769–89. http://dx.doi.org/10.1042/bcj20190543.
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The atherosclerosis prone LDL receptor knockout mice (Ldlr−/−, C57BL/6J background) carry a deletion of the NADP(H)-transhydrogenase gene (Nnt) encoding the mitochondrial enzyme that catalyzes NADPH synthesis. Here we hypothesize that both increased NADPH consumption (due to increased steroidogenesis) and decreased NADPH generation (due to Nnt deficiency) in Ldlr−/− mice contribute to establish a macrophage oxidative stress and increase atherosclerosis development. Thus, we compared peritoneal macrophages and liver mitochondria from three C57BL/6J mice lines: Ldlr and Nnt double mutant, single Nnt mutant and wild-type. We found increased oxidants production in both mitochondria and macrophages according to a gradient: double mutant > single mutant > wild-type. We also observed a parallel up-regulation of mitochondrial biogenesis (PGC1a, TFAM and respiratory complexes levels) and inflammatory (iNOS, IL6 and IL1b) markers in single and double mutant macrophages. When exposed to modified LDL, the single and double mutant cells exhibited significant increases in lipid accumulation leading to foam cell formation, the hallmark of atherosclerosis. Nnt deficiency cells showed up-regulation of CD36 and down-regulation of ABCA1 transporters what may explain lipid accumulation in macrophages. Finally, Nnt wild-type bone marrow transplantation into LDLr−/− mice resulted in reduced diet-induced atherosclerosis. Therefore, Nnt plays a critical role in the maintenance of macrophage redox, inflammatory and cholesterol homeostasis, which is relevant for delaying the atherogenesis process.
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Kanters, Edwin, Marion J. J. Gijbels, Ingeborg van der Made, Monique N. Vergouwe, Peter Heeringa, Georg Kraal, Marten H. Hofker, and Menno P. J. de Winther. "Hematopoietic NF-κB1 deficiency results in small atherosclerotic lesions with an inflammatory phenotype." Blood 103, no. 3 (February 1, 2004): 934–40. http://dx.doi.org/10.1182/blood-2003-05-1450.
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AbstractAtherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-laden macrophages in the vessel wall. One of the major transcription factors in inflammation is nuclear factor κB (NF-κB), and we have studied its role in the development of atherosclerosis. Bone marrow from mice targeted in the NF-κB1 gene encoding for the p50 subunit was used to reconstitute irradiated LDLR-/- mice as a model for atherosclerosis. After feeding the mice a high-fat diet, those deficient in NF-κB1 had a 41% lower rate of atherosclerosis than control mice, as judged by the sizes of the lesions. Furthermore, in the absence of NF-κB1, the lesions were characterized by an inflammatory phenotype, contained increased numbers of small cells, and were almost devoid of normal foam cells. In vitro studies using bone marrow (BM)-derived macrophages showed that macrophages lacking p50 had a prolonged production of tumor necrosis factor (TNF) in response to lipopolysaccharide (LPS), and other cytokines were also affected. Interestingly, the uptake of oxidized low-density lipoprotein (LDL) was greatly reduced in activated p50-deficient macrophages, probably because of a reduction in the expression of scavenger receptor class A. The effects on atherosclerosis might have resulted from the changes in cytokine production and the uptake of modified lipoproteins, making p50 a pivotal regulator of atherogenesis. (Blood. 2004;103:934-940)
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Khyzha, Nadiya, Melvin Khor, Peter V. DiStefano, Liangxi Wang, Ljubica Matic, Ulf Hedin, Michael D. Wilson, Lars Maegdefessel, and Jason E. Fish. "Regulation of CCL2 expression in human vascular endothelial cells by a neighboring divergently transcribed long noncoding RNA." Proceedings of the National Academy of Sciences 116, no. 33 (July 26, 2019): 16410–19. http://dx.doi.org/10.1073/pnas.1904108116.
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Atherosclerosis is a chronic inflammatory disease that is driven, in part, by activation of vascular endothelial cells (ECs). In response to inflammatory stimuli, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway orchestrates the expression of a network of EC genes that contribute to monocyte recruitment and diapedesis across the endothelium. Although many long noncoding RNAs (lncRNAs) are dysregulated in atherosclerosis, they remain poorly characterized, especially in the context of human vascular inflammation. Prior studies have illustrated that lncRNAs can regulate their neighboring protein-coding genes via interaction with protein complexes. We therefore identified and characterized neighboring interleukin-1β (IL-1β)−regulated messenger RNA (mRNA)−lncRNA pairs in ECs. We found these pairs to be highly correlated in expression, especially when located within the same chromatin territory. Additionally, these pairs were predominantly divergently transcribed and shared common gene regulatory elements, characterized by active histone marks and NF-κB binding. Further analysis was performed on lncRNA-CCL2, which is transcribed divergently to the gene, CCL2, encoding a proatherosclerotic chemokine. LncRNA-CCL2 and CCL2 showed coordinate up-regulation in response to inflammatory stimuli, and their expression was correlated in unstable symptomatic human atherosclerotic plaques. Knock-down experiments revealed that lncRNA-CCL2 positively regulated CCL2 mRNA levels in multiple primary ECs and EC cell lines. This regulation appeared to involve the interaction of lncRNA-CCL2 with RNA binding proteins, including HNRNPU and IGF2BP2. Hence, our approach has uncovered a network of neighboring mRNA−lncRNA pairs in the setting of inflammation and identified the function of an lncRNA, lncRNA-CCL2, which may contribute to atherogenesis in humans.
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Lazo-Langner, Alejandro, Greg A. Knoll, Philip S. Wells, Rachel M. Pilkey, Nancy Carson, and Marc A. Rodger. "The Risk of Dialysis Access Thrombosis Is Related to Polymorphisms in the Transforming Growth Factor-β1 and Plasminogen Activator Inhibitor-Type 1 Genes." Blood 106, no. 11 (November 16, 2005): 1631. http://dx.doi.org/10.1182/blood.v106.11.1631.1631.
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Abstract Background. Transforming growth factor-β1 (TGF-β1) is involved in cell growth and differentiation and it plays an important role in the genesis of fibrosis through the stimulation of neointima proliferation and accumulation of components of the extracellular matrix and it has been suggested that polymorphisms (polym) in its gene contribute to determining the patency of the vascular access (VA) in patients (pts) on hemodialysis (HD) by contributing to both atherogenesis and VA thrombosis. On the other hand it has been demonstrated that polym in the gene encoding the plasminogen activator inhibitor type-1 (PAI-1) are a risk factor for ischemic heart disease and possibly stroke although their role in other vascular territories is unknown. It is also known that TGF-β1 is an important up-regulator of the PAI-1 gene. Methods. We conducted a case-control study to determine the relationship between TGF-β1 polym of the signal sequence (869 T>C; 915 G>C) and VA thrombosis in 416 HD pts. (107 with VA thrombosis, 309 controls had no thrombosis). We also explored for possible interactions with the 4G/5G polym of the PAI-1 gene. TGF-β1 and PAI-1 polym were amplified using PCR and genotyped using an ABI PRISM 3100 Genetic Analyzer. TGF-β1 producing haplotypes (haplo) were defined as low, intermediate or high as previously reported. All pts were also tested for thrombophilia. Statistical analysis was done using univariate and multivariate logistic regression adjusted for thrombophilia, age, access type, etc. Results. Frequencies for low, intermediate and high TGF-β1 producing haplo were 9.3, 26.2 and 64.5% in cases and 2.6, 22.3 and 75.1% in controls. Odds of thrombosis for TGF-β1 haplotypes Haplotype Crude OR (95% CI) p Adjusted OR (95% CI) p High producing haplotype is reference category Low 5.11 (1.93, 13.5) 0.001 7.31 (2.15, 24.88) 0.001 Intermediate 1.30 (0.74, 2.29) 0.36 1.39 (0.70, 2.75) 0.35 Figure Figure Frequencies for 5G/5G, 4G/5G and 4G/4G PAI-1 polym. were 21.5, 56.1 and 22.4% in cases and 25.6, 50.2 and 24.3% in controls respectively. When we explored the interaction between both gene polym we found a highly significant result for the interaction between the low TGF-β1 producers and the 4G/4G PAI-1 polym (adjusted OR 19.3; 95% CI 2.82, 132.40; p=0.003). Conclusions. Our results show that intermediate and high producing TGF-β1 haplo have a protective effect against VA thrombosis in HD patients that is not modified by PAI-1 polym and also suggest that the interaction between low TGF-β1 producing haplo and the 4G/4G PAI-1 polym might be an important contributor to thrombosis of the VA in HD pts. Further studies are ongoing to determine the relationship between TGF-β1 haplo, TGF-β1 level, and PAI-1 polym with thrombosis in this and other populations as well as to clarify the mechanisms underlying this apparently paradoxical effect.
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Rauch, Philipp J., Alexander J. Silver, Jk Gopakumar, Marie McConkey, Eti Sinha, Maia Fefer, Eugenia Shvartz, et al. "Loss-of-Function Mutations in Dnmt3a and Tet2 Lead to Accelerated Atherosclerosis and Convergent Macrophage Phenotypes in Mice." Blood 132, Supplement 1 (November 29, 2018): 745. http://dx.doi.org/10.1182/blood-2018-99-118288.
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Abstract Clonal hematopoiesis of indeterminate potential (CHIP) was recently identified as a major risk factor for development of both hematologic malignancies and atherosclerotic cardiovascular disease in humans. The most commonly mutated gene in CHIP, DNMT3A, is a de novo DNA methyltransferase. The second most commonly mutated gene is TET2, an enzyme which can lead to loss of DNA methylation, and thus is thought to have an opposing biochemical function to DNMT3A. Surprisingly, mutations in both genes lead to convergent phenotypes, such as clonal expansion of mutated stem cells, increased risk of malignant transformation, and increased risk of coronary heart disease. A molecular mechanism linking CHIP and cardiovascular disease has been explored only for loss of function mutations in the Tet2 gene (Jaiswal et al., NEJM 2017; Fuster et al., Science 2017). Here we tested the ability of null mutations in Dnmt3a to contribute to atherosclerosis in hypercholesteremic mice. We further explored the biological basis for this association through gene expression analyses and single-cell RNA sequencing. To model cardiovascular disease associated with DNMT3A-mutated CHIP, atherosclerosis-prone Ldlr-/- mice received bone marrow from Dnmt3a+/+ mice (WT), or from Dnmt3a-/- mice (KO) and WT mice in a 1:9 ratio to mimic a typical variant allele fraction observed in human CHIP. Mice then consumed a high-fat, high-cholesterol diet (HFD), and underwent assessment of atherosclerosis. At 9 weeks, mice that had received 10% Dnmt3a-/- bone marrow displayed an average lesion size that was 40% larger compared to mice receiving control marrow only (p=0.04). The increase in lesion size resembles that we previously observed in mice receiving Tet2-/- marrow (Jaiswal et al., NEJM 2017). De novo DNA methylation by Dnmt3a can alter gene expression. To elucidate how such changes may accelerate atherosclerosis, we first performed transcriptome analysis using bulk RNA sequencing of cholesterol-stimulated bone marrow derived macrophages (BMDM) from either WT or KO mice. BMDMs lacking Dnmt3a showed significantly augmented expression of genes belonging to the CXC chemokine cluster, Cxcl1, Cxcl2 and Cxcl3, as well as increases in mRNAs encoding canonical pro-inflammatory cytokines Il1b and Il6. These changes mirrored those we saw in macrophages lacking Tet2 (Jaiswal et al., NEJM 2017). We next asked how transcriptomic changes observed using the ex vivo BMDM system translated into the in vivo lesional environment. Single-cell RNA sequencing (10X Genomics) was performed on atherosclerotic aortae from mice that had been competitively transplanted with WT, Dnmt3a-/-, or Tet2-/- marrow at a 1:9 ratio. Clustering demonstrated broad changes in lesional immune cell composition in mice harboring CHIP. Lack of either Tet2 or Dnmt3a substantially expanded the myeloid compartment, containing cells that drive atherogenesis. A reciprocal reduction mainly affecting T lymphocyte populations accompanied this expansion. Within the myeloid cell compartment, Dnmt3a-/- or Tet2-/- donor cells, but not WT donor cells, gave rise to a distinct lesional macrophage population. These cells expressed markers associated with tissue-resident macrophages (Mrc1, Lyve1, F13a1), but also highly expressed several inflammatory mediators (Cxcl1, Pf4, Ccl2, Ccl7, Ccl8), and a characteristic set of transcription factors (Jun, Fos, Egr1). Overall, the present study reveals broad changes to the lesional cellular composition and transcriptome induced by the most common CHIP mutations, and provides novel insight into the mechanisms by which CHIP accelerates atherosclerosis. Despite exerting opposite catalytic functions, lack of Dnmt3a or of Tet2 function lead to a myriad of similar downstream transcriptomic and cellular changes. These results indicate that mutations in Dnmt3a and Tet2 accelerate atherosclerosis through convergent mechanisms. Disclosures No relevant conflicts of interest to declare.
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Orekhov, Alexander N., Nikita G. Nikiforov, Vasily N. Sukhorukov, Marina V. Kubekina, Igor A. Sobenin, Wei-Kai Wu, Kathy K. Foxx, et al. "Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis." International Journal of Molecular Sciences 21, no. 3 (January 27, 2020): 817. http://dx.doi.org/10.3390/ijms21030817.
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Excessive accumulation of lipid inclusions in the arterial wall cells (foam cell formation) caused by modified low-density lipoprotein (LDL) is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. Recently, we have identified the top 10 master regulators that were involved in the accumulation of cholesterol in cultured macrophages induced by the incubation with modified LDL. It was found that most of the identified master regulators were related to the regulation of the inflammatory immune response, but not to lipid metabolism. A possible explanation for this unexpected result is a stimulation of the phagocytic activity of macrophages by modified LDL particle associates that have a relatively large size. In the current study, we investigated gene regulation in macrophages using transcriptome analysis to test the hypothesis that the primary event occurring upon the interaction of modified LDL and macrophages is the stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response. We identified genes that were up- or downregulated following the exposure of cultured cells to modified LDL or latex beads (inert phagocytosis stimulators). Most of the identified master regulators were involved in the innate immune response, and some of them were encoding major pro-inflammatory proteins. The obtained results indicated that pro-inflammatory response to phagocytosis stimulation precedes the accumulation of intracellular lipids and possibly contributes to the formation of foam cells. In this way, the currently recognized hypothesis that the accumulation of lipids triggers the pro-inflammatory response was not confirmed. Comparative analysis of master regulators revealed similarities in the genetic regulation of the interaction of macrophages with naturally occurring LDL and desialylated LDL. Oxidized and desialylated LDL affected a different spectrum of genes than naturally occurring LDL. These observations suggest that desialylation is the most important modification of LDL occurring in vivo. Thus, modified LDL caused the gene regulation characteristic of the stimulation of phagocytosis. Additionally, the knock-down effect of five master regulators, such as IL15, EIF2AK3, F2RL1, TSPYL2, and ANXA1, on intracellular lipid accumulation was tested. We knocked down these genes in primary macrophages derived from human monocytes. The addition of atherogenic naturally occurring LDL caused a significant accumulation of cholesterol in the control cells. The knock-down of the EIF2AK3 and IL15 genes completely prevented cholesterol accumulation in cultured macrophages. The knock-down of the ANXA1 gene caused a further decrease in cholesterol content in cultured macrophages. At the same time, knock-down of F2RL1 and TSPYL2 did not cause an effect. The results obtained allowed us to explain in which way the inflammatory response and the accumulation of cholesterol are related confirming our hypothesis of atherogenesis development based on the following viewpoints: LDL particles undergo atherogenic modifications that, in turn, accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. Therefore, it became obvious that the primary event in this sequence is not the accumulation of cholesterol but an inflammatory response.
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Antoniades, Charalambos, Cheerag Shirodaria, Thomasz Guzik, Tim Van-Assche, Ravi Pillai, Jorn Lotsch, Dimitris Tousoulis, Christodoulos Stefanadis, Irmgard Tegeder, and Keith M. Channon. "Abstract 5455: A Novel Haplotype on GCH1 Gene, Encoding GTP Cyclohydrolase 1, Regulates Vascular Biopterin Synthesis, eNOS Coupling and Vascular Redox in Human Vessels." Circulation 118, suppl_18 (October 28, 2008). http://dx.doi.org/10.1161/circ.118.suppl_18.s_552-d.
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Background: GTP cyclohydrolase (GTPCH) is a key enzyme in biopterins synthesis, while tetrahydrobiopterin (BH4) is a regulator of eNOS coupling in vascular endothelium. A novel haplotype in GCH1 gene, combining dbSNPs: rs8007267G/A, rs3783641A/T and rs10483639C/G, affects GTPCH activity and biopterins levels in inflammatory cells. We examined the effect of this haplotype on vascular biopterins, eNOS coupling and redox state in human vessels from patients with coronary atherosclerosis. Methods: Samples of saphenous veins (SV) were obtained from 347 patients undergoing CABG. Vasorelaxations of SV to acetylcholine (ACh) and vascular O2- (± eNOS inhibitor LNAME) were determined. Biopterins were measured by HPLC. The haplotypes were defined as X (rs8007267A+ rs3783641T+ rs10483639G) or O (all other haplotypes). Results: The haplotype distribution was OO:245(71%), OX:95(27%) and XX:7(2%). Carriers of the X haplotype had lower plasma (Fig. a ) and vascular (Fig. b ) BH4. The X haplotype was associated with higher vascular O2- (XX+XO: 2.97±0.44 vs OO:1.90±0.10 RLU/Sec/mg, p<0.01), greater LNAME-inhibitable O2- (Fig. c ) suggesting eNOS uncoupling) and lower NO bioavailability (Fig. d ) in human vessels. The X haplotype was also associated with higher plasma ox-LDL (51.0±2.2 in XX+XO vs 44.2±1.4 U/L in OO p<0.05) and lower BH4:total biopterins ratio (43.1±3.2 in XX+XO vs 51.7±2.1% in OO, p<0.05). Conclusions: This novel haplotype on GCH1 gene regulates biopterins biosynthesis in both plasma and vascular endothelium. This haplotype also regulates eNOS coupling, O2- production and NO bioavailability in human vessels, and may play a role in atherogenesis.
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Sukhorukov, V. N., Y. V. Markina, A. M. Markin, M. Bagheri Ekta, V. A. Khotina, A. Y. Postnov, and A. N. Orekhov. "Master regulators in the foam cell formation; the role of phagocytosis." European Heart Journal 41, Supplement_2 (November 1, 2020). http://dx.doi.org/10.1093/ehjci/ehaa946.3768.
Full textAbstract:
Abstract Background Foam cell formation caused by modified LDL is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. 10 inflammation-related master regulators, which were involved in the cholesterol accumulation in cultured macrophages induced by the incubation with modified LDL, have been identified. Objective We hypothesised that the primary event occurring upon the interaction of modified LDL and macrophages is the stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response. Methods Cholesterol accumulation was evaluated in primary macrophages with master regulator genes knock-downed by siRNA for either IL15, EIF2AK3, F2RL1, TSPYL2, or ANXA1. Analysis of enriched transcription factor binding sites in promoters of differentially expressed genes and identification of master regulators in the signal transduction network were performed with TRANSFAC and TRANSPATH databases. Results Genes which were up- or downregulated following the exposure of cultured cells to modified LDL or latex beads were determined. Most of the identified master regulators were involved in the innate immune response, and some of them were encoding major pro-inflammatory proteins. Comparative analysis of master regulators revealed similarities in the genetic regulation of the interaction of macrophages with naturally occurring LDL and desialylated LDL. Oxidized and desialylated LDL affected a different spectrum of genes than naturally occurring LDL. These observations suggest that desialylation is the most important modification of LDL occurring in vivo. Thus, modified LDL caused the gene regulation characteristic of the stimulation of phagocytosis. The knock-down of the EIF2AK3 and IL15 genes completely prevented cholesterol accumulation in cultured macrophages, whereas atherogenic naturally occurring LDL caused significant cholesterol accumulation in the control cells. The ANXA1 gene knock-down caused a further decrease in cholesterol content in cultured macrophages. At the same time, knock-down of F2RL1 and TSPYL2 did not cause an effect. Conclusions The results, showing that inflammatory response and the cholesterol accumulation are related, may confirm our hypothesis of atherogenesis development based on the following viewpoints: LDL particles undergo atherogenic modifications that, in turn, accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. Therefore, it became obvious that the primary event in this sequence is not the accumulation of cholesterol but an inflammatory response. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The Russian Science Foundation