Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis.

Abstract

Patients with diabetes have an increased risk of developing atherosclerosis. Endothelial dysfunction, characterized by the lowered bioavailability of endothelial NO synthase (eNOS)-derived NO, is a critical inducer of atherosclerosis. However, the protective aspect of eNOS in diabetes-associated atherosclerosis remains controversial, a likely consequence of its capacity to release both protective NO or deleterious oxygen radicals in normal and disease settings, respectively. Harnessing the atheroprotective activity of eNOS in diabetic settings remains elusive, in part due to the lack of endogenous eNOS-specific NO release activators. We have recently shown in vitro that eNOS-derived NO release can be increased by blocking its binding to Caveolin-1, the main coat protein of caveolae, using a highly specific peptide, CavNOxin. However, whether targeting eNOS using this peptide can attenuate diabetes-associated atherosclerosis is unknown. In this study, we show that CavNOxin can attenuate atherosclerotic burden by ∼84% in vivo. In contrast, mice lacking eNOS show resistance to CavNOxin treatment, indicating eNOS specificity. Mechanistically, CavNOxin lowered oxidative stress markers, inhibited the expression of proatherogenic mediators, and blocked leukocyte-endothelial interactions. These data are the first to show that endogenous eNOS activation can provide atheroprotection in diabetes and suggest that CavNOxin is a viable strategy for the development of antiatherosclerotic compounds.

• Authors: Arpeeta Sharma, Stephanie Sellers, Nada Stefanovic, Cleo Leung, Sih Min Tan, Olivier Huet, David J Granville, Mark E Cooper, Judy B de Haan, Pascal Bernatchez
• Journal: Diabetes (Diabetes) Vol. 64 Issue 11 Pg. 3937-50 (Nov 2015) ISSN: 1939-327X [Electronic] United States
• PMID: 26116699 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• Caveolin 1
• Nitric Oxide Synthase Type III

Topics

• Animals
• Atherosclerosis (metabolism)
• Caveolae (metabolism)
• Caveolin 1 (metabolism)
• Diabetes Mellitus, Experimental (metabolism)
• Diabetic Angiopathies (metabolism)
• Endothelial Cells (metabolism)
• Endothelium, Vascular (metabolism)
• Humans
• Male
• Mice
• Mice, Knockout
• Nitric Oxide Synthase Type III (metabolism)
• Oxidative Stress (physiology)
• Signal Transduction (physiology)