Uridine-5′-triphosphate (UTP) maintains cardiac mitochondrial function following chemical and hypoxic stress

Previously we found that uridine-5′-triphosphate (UTP) significantly decreased cultured cardiomyocyte death, induced by hypoxia via activating P2Y2 receptors, reduced infarct size and maintained higher ATP levels in an in vivo model. Mitochondrial contribution to the progression of cardiomyocyte injury in ischemia/hypoxia is well known. However, the protective effects of UTP in cardiac cells with a respiratory chain deficiency are poorly elucidated. The aim of our study was to further define the role of UTP on mitochondrial functional tolerance following chemical and/or ischemic stress in in vivo and in vitro models. Cardiac mitochondrial function was tested 24 h post left anterior descending (LAD) ligation in UTP (0.44 μg/kg)-treated rats. UTP's beneficial effect in LAD-ligated hearts was expressed by improved mitochondrial activity (Complexes I, II and IV). In the in vitro model, cultured cardiomyocytes were pretreated with 50 μM UTP prior to hypoxic and/or chemical stress with rotenone or sodium azide. Pretreatment with UTP maintained increased ATP levels as well as mitochondrial membrane potential and reduced lactate dehydrogenase (LDH) release. A modest reduction (12%) in the mitochondrial membrane potential was demonstrated when the cultured cardiomyocytes were subjected to UTP. This reduction was abolished by the P2Y receptor antagonist, reactive blue 2, but not with 5 hydroxydecanoate, a mitochondrial KATP channel inhibitor, or by BAPTA-AM, the intracellular calcium chelator. We suggest that UTP may act as an uncoupling agent, which exerts a modest mitochondrial depolarization, resulting in a reduction of Ca2+ uptake, preserving mitochondrial activity, thereby reducing cell damage during hypoxia.