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Discoidin domain Receptor 2: A determinant of metabolic syndrome-associated arterial fibrosis in non-human primates.

PloS one (2019-12-06)
Mereena George Ushakumary, Mingyi Wang, Harikrishnan V, Allen Sam Titus, Jing Zhang, Lijuan Liu, Robert Monticone, Yushi Wang, Julie A Mattison, Rafael de Cabo, Edward G Lakatta, Shivakumar Kailasam
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Mouse IgG (whole molecule)–Peroxidase antibody produced in rabbit, IgG fraction of antiserum, buffered aqueous solution
Sigma-Aldrich
Transforming Growth Factor-β1 human, TGF-β1, recombinant, expressed in CHO cells, powder, suitable for cell culture
Sigma-Aldrich
MISSION® esiRNA, targeting human DDR2
Sigma-Aldrich
SIS3, ≥98% (HPLC), powder