title: Role of uncoupling protein 3 in ischemia-reperfusion injury, arrhythmias, and preconditioning.
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.
authors: Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Cevher
authors: C
authors: Ozcan
authors: Monica
authors: M
authors: Palmeri
authors: Tamas L
authors: TL
authors: Horvath
authors: Kerry S
authors: KS
authors: Russell
authors: Raymond R
authors: RR
authors: Russell
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000627:therapeutic use; D054059:Coronary Occlusion / Q000503:physiopathology; D066298:In Vitro Techniques; D007473:Ion Channels / Q000235:genetics*; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics*; D009203:Myocardial Infarction / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D018754:Ventricular Dysfunction / Q000235:genetics / Q000503:physiopathology
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604393:Ucp3 protein, mouse; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000255:Adenosine Triphosphate
keywords: energetics; mitochondria