Role of uncoupling protein 3 in ischemia-reperfusion injury, arrhythmias, and preconditioning

Am J Physiol Heart Circ Physiol. 2013 May;304(9):H1192-200. doi: 10.1152/ajpheart.00592.2012. Epub 2013 Mar 1.

Abstract

Overexpression of mitochondrial uncoupling proteins (UCPs) attenuates ischemia-reperfusion (I/R) injury in cultured cardiomyocytes. However, it is not known whether UCPs play an essential role in cardioprotection in the intact heart. This study evaluated the cardioprotective efficacy of UCPs against I/R injury and characterized the mechanism of UCP-mediated protection in addition to the role of UCPs in ischemic preconditioning (IPC). Cardiac UCP3 knockout (UCP3(-/-)) and wild-type (WT) mice hearts were subjected to ex vivo and in vivo models of I/R injury and IPC. Isolated UCP3(-/-) mouse hearts were retrogradely perfused and found to have poorer recovery of left ventricular function compared with WT hearts under I/R conditions. In vivo occlusion of the left coronary artery resulted in twofold larger infarcts in UCP3(-/-) mice compared with WT mice. Moreover, the incidence of in vivo I/R arrhythmias was higher in UCP3(-/-) mice. Myocardial energetics were significantly impaired with I/R, as reflected by a decreased ATP content and an increase in the AMP-to-ATP ratio. UCP3(-/-) hearts generated more reactive oxygen species (ROS) than WT hearts during I/R. Pretreatment of UCP3(-/-) hearts with the pharmacological uncoupling agent carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone improved postischemic functional recovery. Also the protective efficacy of IPC was abolished in UCP3(-/-) mice. We conclude that UCP3 plays a critical role in cardioprotection against I/R injury and the IPC phenomenon. There is increased myocardial vulnerability to I/R injury in hearts lacking UCP3. The mechanisms of UCP3-mediated cardioprotection include regulation of myocardial energetics and ROS generation by UCP3 during I/R.

Keywords: energetics; mitochondria.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / metabolism
  • Arrhythmias, Cardiac / physiopathology
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / therapeutic use
  • Coronary Occlusion / physiopathology
  • In Vitro Techniques
  • Ion Channels / genetics*
  • Ischemic Preconditioning, Myocardial*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondrial Proteins / genetics*
  • Myocardial Infarction / drug therapy
  • Myocardial Infarction / genetics
  • Myocardial Infarction / physiopathology
  • Myocardial Reperfusion Injury / drug therapy
  • Myocardial Reperfusion Injury / genetics*
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / physiopathology
  • Myocytes, Cardiac / metabolism
  • Reactive Oxygen Species / metabolism
  • Uncoupling Protein 2
  • Uncoupling Protein 3
  • Ventricular Dysfunction / genetics
  • Ventricular Dysfunction / physiopathology

Substances

  • Ion Channels
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • Ucp3 protein, mouse
  • Uncoupling Protein 2
  • Uncoupling Protein 3
  • Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
  • Adenosine Triphosphate