Obesity-induced vascular dysfunction and arterial stiffening requires endothelial cell arginase 1. Issue 13 (7th September 2017)

• Record Type: Journal Article
• Authors: Bhatta, Anil; Yao, Lin; Xu, Zhimin; Toque, Haroldo A.; Chen, Jijun; Atawia, Reem T.; Fouda, Abdelrahman Y.; Bagi, Zsolt; Lucas, Rudolf; Caldwell, Ruth B.; Caldwell, Robert W.
• Is Part Of: Cardiovascular research. Volume 113:Issue 13(2017)
• Page Start: 1664
• Page End: 1676
• Publication Date: 2017-09-07
• Subjects: Obesity -- Vascular dysfunction -- Arginase -- Fibrosis -- Diabetes; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvx164
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: Elevation of arginase activity has been linked to vascular dysfunction in diabetes and hypertension by a mechanism involving decreased nitric oxide (NO) bioavailability due to L-arginine depletion. Excessive arginase activity also can drive L-arginine metabolism towards the production of ornithine, polyamines, and proline, promoting proliferation of vascular smooth muscle cells and collagen formation, leading to perivascular fibrosis. We hypothesized that there is a specific involvement of arginase 1 expression within the vascular endothelial cells in this pathology. Methods and results: To test this proposition, we used models of type 2 diabetes and metabolic syndrome. Studies were performed using wild type (WT), endothelial-specific arginase 1 knockout (EC-A1 − / − ) and littermate controls(A1 con ) mice fed high fat-high sucrose (HFHS) or normal diet (ND) for 6 months and isolated vessels exposed to palmitate-high glucose (PA/HG) media. Some WT mice or isolated vessels were treated with an arginase inhibitor, ABH [2-(S)-amino-6-boronohexanoic acid. In WT mice, the HFHS diet promoted increases in body weight, fasting blood glucose, and post-prandial insulin levels along with arterial stiffening and fibrosis, elevated blood pressure, decreased plasma levels of L-arginine, and elevated L-ornithine. The HFHS diet or PA/HG treatment also induced increases in vascular arginase activity along with oxidative stress, reduced vascular NO levels, and impaired endothelial-dependent vasorelaxation. All of these effects except obesity and hypercholesterolemia were prevented or significantly reduced by endothelial-specific deletion of arginase 1 or ABH treatment. Conclusion: Vascular dysfunctions in diet-induced obesity are prevented by deletion of arginase 1 in vascular endothelial cells or arginase inhibition. These findings indicate that upregulation of arginase 1 expression/activity in vascular endothelial cells has an integral role in diet-induced cardiovascular dysfunction and metabolic syndrome.