Endothelial dysfunction induces atherosclerosis: increased aggrecan expression promotes apoptosis in vascular smooth muscle cells
2
조회
0
다운로드
2
인용
0
참고문헌
키워드
초록
Endothelial dysfunction-induced lipid retention is an early feature of atherosclerotic lesion formation. Apoptosis of vascular smooth muscle cells (VSMCs) is one of the major modulating factors of atherogenesis, which accelerates atherosclerosis progression by causing plaque destabilization and rupture. However, the mechanism underlying VSMC apoptosis mediated by endothelial dysfunction in relation to atherosclerosis remains elusive. In this study, we reveal differential expression of several genes related to lipid retention and apoptosis, in conjunction with atherosclerosis, by utilizing a genetic mouse model of endothelial nitric oxide synthase (eNOS) deficiency manifesting endothelial dysfunction. Moreover, eNOS deficiency led to the enhanced susceptibility against pro-apoptotic insult in VSMCs. In particular, the expression of aggrecan, a major proteoglycan, was elevated in aortic tissue of eNOS deficient mice compared to wild type mice, and administration of aggrecan induced apoptosis in VSMCs. This suggests that eNOS deficiency may elevate aggrecan expression, which promotes apoptosis in VSMC, thereby contributing to atherosclerosis progression. These results may facilitate the development of novel approaches for improving the diagnosis or treatment of atherosclerosis.
Abstract
Endothelial dysfunction-induced lipid retention is an early feature of atherosclerotic lesion formation. Apoptosis of vascular smooth muscle cells (VSMCs) is one of the major modulating factors of atherogenesis, which accelerates atherosclerosis progression by causing plaque destabilization and rupture. However, the mechanism underlying VSMC apoptosis mediated by endothelial dysfunction in relation to atherosclerosis remains elusive. In this study, we reveal differential expression of several genes related to lipid retention and apoptosis, in conjunction with atherosclerosis, by utilizing a genetic mouse model of endothelial nitric oxide synthase (eNOS) deficiency manifesting endothelial dysfunction. Moreover, eNOS deficiency led to the enhanced susceptibility against pro-apoptotic insult in VSMCs. In particular, the expression of aggrecan, a major proteoglycan, was elevated in aortic tissue of eNOS deficient mice compared to wild type mice, and administration of aggrecan induced apoptosis in VSMCs. This suggests that eNOS deficiency may elevate aggrecan expression, which promotes apoptosis in VSMC, thereby contributing to atherosclerosis progression. These results may facilitate the development of novel approaches for improving the diagnosis or treatment of atherosclerosis.
참고문헌 (25)
- Furchgott RF, "The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine", Nature, 288, pp.373~376 (1980)
- Davignon J, "Role of endothelial dysfunction in atherosclerosis", Circulation, 109, pp.iii27~iii32 (2004)
- Mooradian DL, "Nitric oxide(NO)donor molecules : effect of NO release rate on vascular smooth muscle cell proliferation in vitro", J Cardiovasc Pharmacol, 25, pp.674~678 (1995)
- Ponnuswamy P, "eNOS protects from atherosclerosis despite relevant superoxide production by the enzyme in apoE mice", PLoS One, 7, pp.e30193~ (2012)
- Flammer AJ, "The assessment of endothelial function : from research into clinical practice", Circulation, 126, pp.753~767 (2012)
- Bogaty P, "Vasoreactivity of the culprit lesion in unstable angina", Circulation, 90, pp.5~11 (1994)
- Cooke JP, "Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit", J Clin Invest, 90, pp.1168~1172 (1992)
- Lusis AJ, "Atherosclerosis", Nature, 407, pp.233~241 (2000)
- Libby P, "Progress and challenges in translating the biology of atherosclerosis", Nature, 473, pp.317~325 (2011)
- Clarke MC, "Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis", Nat Med, 12, pp.1075~1080 (2006)
- Klouche M, "Modified atherogenic lipoproteins induce expression of pentraxin-3by human vascular smooth muscle cells", Atherosclerosis, 175, pp.221~228 (2004)
- Zhang MJ, "Impaired SIRT1promotes the migration of vascular smooth muscle cell-derived foam cells", Histochem Cell Biol, 146, pp.33~43 (2016)
- Kockx MM, "Apoptosis in atherosclerosis: beneficial or detrimental?", Cardiovasc Res, 45, pp.736~746 (2000)
- Martinet W, "Apoptosis in atherosclerosis : focus on oxidized lipids and inflammation", Curr Opin Lipidol, 12, pp.535~541 (2001)
- Martinet W, "Autophagy in atherosclerosis : a cell survival and death phenomenon with therapeutic potential", Circ Res, 104, pp.304~317 (2009)
- Littlewood TD, "Apoptotic cell death in atherosclerosis", Curr Opin Lipidol, 14, pp.469~475 (2003)
- Kuhlencordt PJ, "Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E", endothelial nitric oxide synthase double-knockout mice, 2001, pp.104, 448~454
- Strom A, "Extracellular matrix components in atherosclerotic arteries of Apo E", LDL receptor deficient mice : an immunohistochemical study, 2004, pp.19, 337~347
- Talusan P, "Analysis of intimal proteoglycans in atherosclerosis-prone and atherosclerosisresistant human arteries by mass spectrometry", Mol Cell Proteomics, 4, pp.1350~1357 (2005)
- Cao L, "Chondrocyte apoptosis induced by aggrecan G1 domain as a result of decreased cell adhesion", Exp Cell Res, 246, pp.527~537 (1999)
- Fujimoto T, "CD44binds a chondroitin sulfate proteoglycan, aggrecan", Int Immunol, 13, pp.359~366 (2001)
- Didangelos A, "Novel role of ADAMTS-5 protein in proteoglycan turnover and lipoprotein retention in atherosclerosis", J Biol Chem, 287, pp.19341~19345 (2012)
- Stevens AL, "Nitric oxide enhances aggrecan degradation by aggrecanase in response to TNF-alpha but not IL-1beta treatment at a post-transcriptional level in bovine cartilage explants", Osteoarthritis Cartilage, 16, pp.489~497 (2008)
- Ross R, "A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro", Proc Natl Acad Sci U S A, 71, pp.1207~1210 (1974)
- Gentleman RC, "Bioconductor : open software development for computational biology and bioinformatics", Genome Biol, 5, pp.R80~ (2004)