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Endothelial dysfunction induces atherosclerosis: increased aggrecan expression promotes apoptosis in vascular smooth muscle cells
Sang-Min Kim1,4,#, Jae-Wan Huh2,#, Eun-Young Kim1,3, Min-Kyung Shin1,3, Ji-Eun Park1,3, Seong Who Kim2,3, Bongkun Choi1,3, Wooseong Lee2, Bongkun Choi1,3, Eun-Ju Chang1,2,3,*
1Department of Biomedical Sciences and 2Department of Biochemistry and Molecular Biology and 3Stem Cell Immunomodulation Research Center, University of Ulsan College of Medicine,
4Department of Pathology, Yonsei University College of Medicine
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.
Abstract, Accepted Manuscript [Submitted on December 6, 2018, Accepted on December 26, 2018]
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