Skip to Content
Merck
  • Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis.

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

Diabetes (2015-06-28)
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
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Formaldehyde solution, for molecular biology, 36.5-38% in H2O
Supelco
Formaldehyde solution, stabilized with methanol, ~37 wt. % in H2O, certified reference material
Sigma-Aldrich
Formaldehyde solution, meets analytical specification of USP, ≥34.5 wt. %
Sigma-Aldrich
Formaldehyde solution, ACS reagent, 37 wt. % in H2O, contains 10-15% Methanol as stabilizer (to prevent polymerization)
Sigma-Aldrich
Formaldehyde solution, for molecular biology, BioReagent, ≥36.0% in H2O (T)
Sigma-Aldrich
Formaldehyde-12C solution, 20% in H2O, 99.9 atom % 12C
SAFC
Formaldehyde solution, contains 10-15% methanol as stabilizer, 37 wt. % in H2O
Sigma-Aldrich
Hematoxylin, certified by the Biological Stain Commission
Sigma-Aldrich
Hematoxylin
Sigma-Aldrich
3,3′-Diaminobenzidine tetrahydrochloride, tablet, 10 mg substrate per tablet