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

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.

• Authors: 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
• Journal: PloS one (PLoS One) Vol. 14 Issue 12 Pg. e0225911 ( 2019) ISSN: 1932-6203 [Electronic] United States
• PMID: 31805124 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen Type I
• Discoidin Domain Receptor 2

Topics

• Animals
• Arteries (metabolism, pathology)
• Collagen Type I (genetics, metabolism)
• Discoidin Domain Receptor 2 (genetics, metabolism)
• Disease Models, Animal
• Disease Susceptibility
• Fibroblasts (metabolism)
• Fibrosis
• Male
• Metabolic Syndrome (complications, genetics, metabolism)
• Primates
• Vascular Diseases (etiology, pathology)