Abstract 241: Intermittent Hypoxia Protects Cardiomyocytes Against Ischemia/Reperfusion-Induced Ca2+ Overload and Contraction Suppression via Activation of α1b-adrenoceptors
We have demonstrated that long-term training to intermittent high altitude hypoxia (IH) protects hearts against ischemia-reperfusion (I/R)-induced Ca2+ 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 Ca2+ overload via activation of α1-adrenoceptor (α1-ARs) pathways. To test it, dynamics of cytosolic free Ca2+ concentration ([Ca2+]c), mitochondrial [Ca2+] ([Ca2+]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 [Ca2+]c and [Ca2+]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 Ca2+ transients and cell shortening was markedly attenuated by IH, with decreases in mitochondrial cytochrome c release and ATP reduction during reperfusion. Meanwhile, the α1B-AR and α1D-AR density obviously decreased during ischemia, while α1A-AR density remained unchanged. IH did not change α1A-AR density, but increased α1B-AR density by ~50% and decreased α1D-AR density further by 30% during I/R. Moreover, IH-induced protections were abolished by α1B-AR antagonist chloroethylclonidine but not α1A- or α1D-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 (mitoKATP) channels with 5-hydroxydecanoate, a downstream signaling pathway and effector of α1-ARs. Our findings indicate that α1B-AR subtype might be one of the important mediators in IH protects myocytes against I/R injury via maintaining intracellular Ca2+ homeostasis and protecting the ability of mitochondria through activation of the α1B-ARs and PKCϵ pathway as well as mitoKATP channel.. by via translocation of PKCϵ and opening of mitoKATP channels. Mitochondrial function appears to be a determinant of cardioprotection induced by IH.