Goshovska Y. Role of uncoupling proteins UCP2 and UCP3 in heart function in aging and ischemia-reperfusion.

The present study is a result of experimental attempt to reveal the role of uncoupling proteins (UCP2 and UCP3) in heart function with aging and during ischemia-reperfusion. For the first time it was shown that cardiac UCP2 and UCP3 genes expression was increased with aging (by 39% and 29% respectively). Impaired function of aged rat hearts was accompanied with increased oxygen consumption (by 30%, P<0.05), oxygen cost of myocardial work (by 25%, P<0.05) and lowered mitochondrial membrane potential (delta psi m = -146,5 3,2 mV comparing with -156,5 3,5 mV in adult rats; Р<0.05). Isolated rat hearts of adult (6 mo) and old (24 mo) were perfused by Langendorf preparation and subjected to ischemia-reperfusion. For the firs time we demonstrated that 20 min ischemia stimulated expression of UCPs genes in 6mo-aged myocardium: mRNA levels of UCP2 and UCP3 were significantly higher (by 53% and 40% correspondingly, Р<0.05) that those in control, whereas there was no such effect in 24mo-aged hearts. Inhibition of UCP2 was performed using genipin addition to perfusion solution in dose of 10-5M. It was observed that genipin depressed heart function in dose-dependent manner of both age groups, although much more in 6mo-old one. Dyastolic dysfunction caused by genipin application is an evidence of damage of the contractile apparatus of cardiomyocytes and could indirectly point to the role of UCPs in calcium uptake. Furthermore, reperfusion disturbances of heart function, coronary flow, contractile activity of myocardium and non-effective oxygen utilization were intensive in genipin pretreated 24-mo aged hearts. For the first time we showed that UCP2 and UCP3 genes expression in 6mo-aged rat heart was elevated after ischemic precondition, whereas there was no such effect in 24mo-aged hearts. Inhibition of UCP2 with genipin abolished cardioprotective effect of ischemic preconditioning and prevented effective heart function restoration during reperfusion. Thus, obtained data indicate the protective role of UCPs activation during oxidative stress induced by aging or ischemia-reperfusion. We consider that cardiac UCPs may be engaged in protective pathways of ischemic preconditioning.