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Mitochondria selective S-nitrosation by mitochondria-targeted S-nitrosothiol protects against post-infarct heart failure in mouse hearts.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Methner, Carmen 
Chouchani, Edward T 
Buonincontri, Guido 
Pell, Victoria R 
Sawiak, Stephen J 

Abstract

AIMS: Recently it has been shown that the mitochondria-targeted S-nitrosothiol MitoSNO protects against acute ischaemia/reperfusion (IR) injury by inhibiting the reactivation of mitochondrial complex I in the first minutes of reperfusion of ischaemic tissue, thereby preventing free radical formation that underlies IR injury. However, it remains unclear how this transient inhibition of mitochondrial complex I-mediated free radicals at reperfusion affects the long-term recovery of the heart following IR injury. Here we determined whether the acute protection by MitoSNO at reperfusion prevented the subsequent development of post-myocardial infarction heart failure. METHODS AND RESULTS: Mice were subjected to 30 min left coronary artery occlusion followed by reperfusion and recovery over 28 days. MitoSNO (100 ng/kg) was applied 5 min before the onset of reperfusion followed by 20 min infusion (1 ng/kg/min). Infarct size and cardiac function were measured by magnetic resonance imaging (MRI) 24 h after infarction. MitoSNO-treated mice exhibited reduced infarct size and preserved function. In addition, MitoSNO at reperfusion improved outcome measures 28 days post-IR, including preserved systolic function (63.7 ±1.8% LVEF vs. 53.7 ± 2.1% in controls, P = 0.01) and tissue fibrosis. CONCLUSIONS: MitoSNO action acutely at reperfusion reduces infarct size and protects from post-myocardial infarction heart failure. Therefore, targeted inhibition of mitochondrial complex I in the first minutes of reperfusion by MitoSNO is a rational therapeutic strategy for preventing subsequent heart failure in patients undergoing IR injury.

Description

Keywords

Free radicals, Heart failure, Magnetic resonance imaging, Myocardial infarction, Nitric oxide, Animals, Coronary Occlusion, Electron Transport Complex I, Free Radicals, Heart, Heart Failure, Magnetic Resonance Imaging, Cine, Mice, Mitochondria, Mitochondrial Proteins, Myocardial Infarction, Myocardial Reperfusion Injury, Myocardium, Myocytes, Cardiac, Nitric Oxide Donors, Nitrosation, S-Nitrosothiols

Journal Title

Eur J Heart Fail

Conference Name

Journal ISSN

1388-9842
1879-0844

Volume Title

16

Publisher

Wiley
Sponsorship
British Heart Foundation (None)
Medical Research Council (MC_U105663142)