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 P2Y(2) 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 microg/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 microM 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 K(ATP) 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 Ca(2+) uptake, preserving mitochondrial activity, thereby reducing cell damage during hypoxia.
Yitzhaki
Smadar
S
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 52900 Israel.
Hochhauser
Edith
E
Porat
Eyal
E
Shainberg
Asher
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D003576:Electron Transport Complex IV / Q000032:analysis; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008564:Membrane Potentials / Q000502:physiology; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D014544:Uridine Triphosphate / Q000494:pharmacology / Q000502:physiology*
D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D003576:Electron Transport Complex IV; D014544:Uridine Triphosphate