Diabetes/high glucose induced arginase increases arterial smooth muscle cell proliferation and collagen synthesis/fibrosis through ornithine decarboxylase and ornithine aminotransferase pathways

Abstract

Arginase can compete with nitric oxide (NO) synthase for their common substrate, L‐arginine, and its increased activity can decrease NO production. Arginase also provides ornithine for synthesis of polyamines via ornithine decarboxylase (ODC) and proline/collagen via ornithine aminotransferase (OAT). We hypothesize that diabetes/high glucose (HG) induce vascular wall thickening and fibrosis through increased level of arginase‐derived ornithine available for ODC and OAT. We exposed rat aortic smooth muscle cells to HG (25 mM), which resulted in increased arginase activity (57%), cell proliferation (22%), and ODC mRNA (25%). Treatment with arginase inhibitor BEC (S‐(2‐boronoethyl)‐l‐cysteine) prevented these changes. We observed increased perivascular fibrosis (68%) in coronary arteries of 8‐week wild‐type (WT) diabetic mice compared to arginase I partial knockout (AI+/−) diabetic mice. Aorta from diabetic WT mice also exhibited impaired endothelium‐dependent relaxation (EDR) compared to control (maximum EDR: 32.9% vs 61.8%). EDR was largely maintained in aorta from diabetic AI+/− mice. Furthermore, adenoviral overexpression of arginase I in isolated aorta concomitantly increased ODC expression, implying an effect of arginase on ODC. In conclusion, arginase appears to have important roles in HG/diabetes‐induced vascular dysfunction, proliferation and fibrosis through ODC and OAT pathway.