Article Text

PDF
6 S-Nitrosation of a Cysteine Switch on Mitochondrial Complex I Protects from Acute Ischaemia-Reperfusion Damage and Post Myocardial Infarction Heart Failure
  1. E T Chouchani1,2,
  2. V R Pell1,
  3. C Methner1,
  4. G Buonincontri1,3,
  5. M P Murphy2,
  6. T Krieg1
  1. 1Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
  2. 2MRC Mitochondrial Biology Unit, Hills Road, Cambridge, UK
  3. 3Wolfson Brain Imaging Centre, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

Abstract

Oxidative damage from elevated production of reactive oxygen species contributes to ischemia-reperfusion injury (IRI) in myocardial infarction (MI) and stroke. We recently determined a critical mechanism for protection from acute IRI by S-nitrosation using a mitochondria-selective S-nitrosating agent, MitoSNO. Protection by MitoSNO is afforded by inhibition of complex I through selective S-nitrosation of Cys39 on the ND3 subunit, which becomes susceptible to modification only after ischaemia (1). Here, we determine that MitoSNO action acutely at reperfusion can also prevent the development of post-MI heart failure in mice. Cardiac function and morphology was assessed 24 h post-infarction by late gadolinium-enhanced magnetic resonance imaging. The resulting infarct size was significantly smaller in the group treated with MitoSNO during early reperfusion (bolus of 100 ng/kg, followed by 2 h infusion of 1 ng/kg/min). Furthermore, left ventricular ejection fraction (EF) was increased with MitoSNO treatment from 51.3 ± 2.1% in controls to 64.4% ± 1.9, p = 0.001, and this increase was still present when the hearts were reassessed via cardiac MRI after 28 days. In addition, MitoSNO-treated hearts showed significantly less tissue fibrosis after 28 days. Taken together, reversible S-nitrosation of complex I ND3 Cys39 results in significant protection from acute and long-term effects of IRI. In demonstrating amelioration of clinically relevant end points of post-MI heart failure, we provide evidence for MitoSNO to be a promising rational therapeutic strategy for translation to use in humans.

Reference

  1. Chouchani et al. (2013) Nature Medicine, 19-753-759.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.