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

• Published in: American journal of physiology. Heart and circulatory physiology 2013-05, Vol.304 (9), p.H1192-H1200
• Main Authors: Ozcan, Cevher, Palmeri, Monica, Horvath, Tamas L, Russell, Kerry S, Russell, 3rd, Raymond R
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - physiopathology; Call for Papers; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone - therapeutic use; Cardiac arrhythmia; Cardiomyocytes; Coronary Occlusion - physiopathology; In Vitro Techniques; Ion Channels - genetics; Ischemic Preconditioning, Myocardial; Male; Mice; Mice, Inbred C57BL; Mitochondrial DNA; 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; Physiology; Proteins; Reactive Oxygen Species - metabolism; Rodents; Uncoupling Protein 2; Uncoupling Protein 3; Ventricular Dysfunction - genetics; Ventricular Dysfunction - physiopathology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00592.2012

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.