Induction of caveolin-3/eNOS complex by nitroxyl (HNO) ameliorates diabetic cardiomyopathy.

Abstract

Nitroxyl (HNO), one-electron reduced and protonated sibling of nitric oxide (NO), is a potential regulator of cardiovascular functions. It produces positive inotropic, lusitropic, myocardial anti-hypertrophic and vasodilator properties. Despite of these favorable actions, the significance and the possible mechanisms of HNO in diabetic hearts have yet to be fully elucidated. H9c2 cells or primary neonatal mouse cardiomyocytes were incubated with normal glucose (NG) or high glucose (HG). Male C57BL/6 mice received intraperitoneal injection of streptozotocin (STZ) to induce diabetes. Here, we demonstrated that the baseline fluorescence signals of HNO in H9c2 cells were reinforced by both HNO donor Angeli's salt (AS), and the mixture of hydrogen sulfide (H2S) donor sodium hydrogen sulfide (NaHS) and NO donor sodium nitroprusside (SNP), but decreased by HG. Pretreatment with AS significantly reduced HG-induced cell vitality injury, apoptosis, reactive oxygen species (ROS) generation, and hypertrophy in H9c2 cells. This effect was mediated by induction of caveolin-3 (Cav-3)/endothelial nitric oxide (NO) synthase (eNOS) complex. Disruption of Cav-3/eNOS by pharmacological manipulation or small interfering RNA (siRNA) abolished the protective effects of AS in HG-incubated H9c2 cells. In STZ-induced diabetic mice, administration of AS ameliorated the development of diabetic cardiomyopathy, as evidenced by improved cardiac function and reduced cardiac hypertrophy, apoptosis, oxidative stress and myocardial fibrosis without affecting hyperglycemia. This study shed light on how interaction of NO and H2S regulates cardiac pathology and provide new route to treat diabetic cardiomyopathy with HNO.

• Authors: Hai-Jian Sun, Si-Ping Xiong, Zhi-Yuan Wu, Lei Cao, Meng-Yuan Zhu, Philip K Moore, Jin-Song Bian
• Journal: Redox biology (Redox Biol) Vol. 32 Pg. 101493 (05 2020) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 32182574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Cav3 protein, mouse
• Cav3 protein, rat
• Caveolin 3
• Nitrogen Oxides
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• Nos3 protein, rat
• nitroxyl

Topics

• Animals
• Caveolin 3
• Diabetes Mellitus, Experimental (drug therapy)
• Diabetic Cardiomyopathies (drug therapy)
• Male
• Mice
• Mice, Inbred C57BL
• Nitric Oxide Synthase Type III
• Nitrogen Oxides
• Rats