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

TitleMitochondria selective S-nitrosation by mitochondria-targeted S-nitrosothiol protects against post-infarct heart failure in mouse hearts.
Publication TypeJournal Article
Year of Publication2014
AuthorsMethner, C, Chouchani, ET, Buonincontri, G, Pell, VR, Sawiak, SJ, Murphy, MP, Krieg, T
JournalEur J Heart Fail
Volume16
Issue7
Pagination712-7
Date Published2014 Jul
ISSN1879-0844
KeywordsAnimals, 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
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.

DOI10.1002/ejhf.100
Alternate JournalEur. J. Heart Fail.
Citation Key10.1002/ejhf.100
PubMed ID24891297
PubMed Central IDPMC4231226
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom
PG/12/42/29655 / / British Heart Foundation / United Kingdom