Discoidin domain Receptor 2: A determinant of metabolic syndrome-associated arterial fibrosis in non-human primates
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Mereena George Ushakumary aff001; Mingyi Wang aff002; Harikrishnan V aff001; Allen Sam Titus aff001; Jing Zhang aff002; Lijuan Liu aff002; Robert Monticone aff002; Yushi Wang aff002; Julie A. Mattison aff004; Rafael de Cabo aff004; Edward G. Lakatta aff002; Shivakumar Kailasam aff001
Působiště autorů:
Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India
aff001; Laboratory of Cardiovascular Science, National Institute on Aging, National Institute on Aging/National Institutes of Health, Baltimore, Maryland, United States of America
aff002; Department of Cardiology, The First Hospital of Jilin University, Changchun, China
aff003; Translational Gerontology Branch, National Institute on Aging, National Institute on Aging/National Institutes of Health, Baltimore, Maryland, United States of America
aff004
Vyšlo v časopise:
PLoS ONE 14(12)
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pone.0225911
Souhrn
Collagen accumulation and remodeling in the vascular wall is a cardinal feature of vascular fibrosis that exacerbates the complications of hypertension, aging, diabetes and atherosclerosis. With no specific therapy available to date, identification of mechanisms underlying vascular fibrogenesis is an important clinical goal. Here, we tested the hypothesis that Discoidin Domain Receptor 2 (DDR2), a collagen-specific receptor tyrosine kinase, is a determinant of arterial fibrosis. We report a significant increase in collagen type 1 levels along with collagen and ECM remodeling, degradation of elastic laminae, enhanced fat deposition and calcification in the abdominal aorta in a non-human primate model of high-fat, high-sucrose diet (HFS)-induced metabolic syndrome. These changes were associated with a marked increase in DDR2. Resveratrol attenuated collagen type I deposition and remodeling induced by the HFS diet, with a concomintant reduction in DDR2. Further, in isolated rat vascular adventitial fibroblasts and VSMCs, hyperglycemia increased DDR2 and collagen type I expression via TGF-β1/SMAD2/3, which was attenuated by resveratrol. Notably, gene knockdown and overexpression approaches demonstrated an obligate role for DDR2 in hyperglycemia-induced increase in collagen type I expression in these cells. Together, our observations point to DDR2 as a hitherto unrecognized molecular link between metabolic syndrome and arterial fibrosis, and hence a therapeutic target.
Klíčová slova:
Gene expression – Diet – Analysis of variance – Fibroblasts – Collagens – Fibrosis – Protein expression – Monkeys
Zdroje
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