title: Mitochondria selective S-nitrosation by mitochondria-targeted S-nitrosothiol protects against post-infarct heart failure in mouse hearts.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Carmen
authors.initials: C
authors.lastname: Methner
authors.forename: Edward T
authors.initials: ET
authors.lastname: Chouchani
authors.forename: Guido
authors.initials: G
authors.lastname: Buonincontri
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Pell
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sawiak
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
mesh_terms: D000818:Animals; D054059:Coronary Occlusion; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D005609:Free Radicals / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D019028:Magnetic Resonance Imaging, Cine; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D015538:Nitrosation; D026403:S-Nitrosothiols / Q000494:pharmacology*
chemical_list: D005609:Free Radicals; D024101:Mitochondrial Proteins; D020030:Nitric Oxide Donors; D026403:S-Nitrosothiols; D042967:Electron Transport Complex I
keywords: Free radicals; Heart failure; Magnetic resonance imaging; Myocardial infarction; Nitric oxide