Abstract 241: Intermittent Hypoxia Protects Cardiomyocytes Against Ischemia/Reperfusion-Induced Ca 2+ Overload and Contraction Suppression via Activation of α 1b -adrenoceptors

Abstract

We have demonstrated that long-term training to intermittent high altitude hypoxia (IH) protects hearts against ischemia-reperfusion (I/R)-induced Ca 2+ overload and improved postischemic myocardial contractility. This cardioprotection is non-invasive and maintains much longer time compared with that induced by ischemic preconditioning, thereby, it may have great clinical potential. However, its precise signaling pathways are not fully clarified. Here we hypothesized that IH may attenuate I/R-induced cytosolic and mitochondrial Ca 2+ overload via activation of α 1 -adrenoceptor (α 1 -ARs) pathways. To test it, dynamics of cytosolic free Ca 2+ concentration ([Ca 2+ ] c ), mitochondrial [Ca 2+ ] ([Ca 2+ ] m ) and cell contraction were examined during preischemia and I/R in ventricular cardiomyocytes from normoxic and IH rats. IH significantly attenuated I/R-induced [Ca 2+ ] c and [Ca 2+ ] m overload by 63.5 ± 3.6% and 57.0 ± 4.5% at 30 min of reperfusion (R30), respectively. Consistently, I/R-induced depression on Ca 2+ transients and cell shortening was markedly attenuated by IH, with decreases in mitochondrial cytochrome c release and ATP reduction during reperfusion. Meanwhile, the α 1B -AR and α 1D -AR density obviously decreased during ischemia, while α 1A -AR density remained unchanged. IH did not change α 1A -AR density, but increased α 1B -AR density by ~50% and decreased α 1D -AR density further by 30% during I/R. Moreover, IH-induced protections were abolished by α 1B -AR antagonist chloroethylclonidine but not α 1A - or α 1D -AR antagonist. Furthermore, IH-afforded protection was lost when epsilon isoform of protein kinase C (PKCϵ) was inhibited with PKCϵ V1–2 and mitochondrial ATP sensitive potassium (mitoK ATP ) channels with 5-hydroxydecanoate, a downstream signaling pathway and effector of α 1 -ARs. Our findings indicate that α 1B -AR subtype might be one of the important mediators in IH protects myocytes against I/R injury via maintaining intracellular Ca 2+ homeostasis and protecting the ability of mitochondria through activation of the α 1B -ARs and PKCϵ pathway as well as mitoK ATP channel.. by via translocation of PKCϵ and opening of mitoK ATP channels. Mitochondrial function appears to be a determinant of cardioprotection induced by IH.