PKCε Promotes Cardiac Mitochondrial and Metabolic Adaptation to Chronic Hypobaric Hypoxia by GSK3β Idnhibition

PKC epsilon is central to cardioprotection. Sub-proteome analysis demonstrated co-localization of activated cardiac PKC epsilon (aPKC epsilon) with metabolic, mitochondrial, and cardioprotective modulators like hypoxia-inducible factor 1 alpha (HIF-1 alpha). aPKC epsilon relocates to the mitochondrion, inactivating glycogen synthase kinase 3 beta (GSK3 beta) to modulate glycogen metabolism, hypertrophy and HIF-1 alpha. However, there is no established mechanistic link between PKC epsilon, p-GSK3 beta and HIF1-alpha. Here we hypothesized that cardiac-restricted aPKC epsilon improves mitochondrial response to hypobaric hypoxia by altered substrate fuel selection via a GSK3 beta/HIF-1 alpha-dependent mechanism. aPKC epsilon and wild-type (WT) mice were exposed to 14 days of hypobaric hypoxia (45 kPa, 11% O(2)) and cardiac metabolism, functional parameters, p-GSK3 beta/HIF-1 alpha expression, mitochondrial function and ultrastructure analyzed versus normoxic controls. Mitochondrial ADP-dependent respiration, ATP production and membrane potential were attenuated in hypoxic WT but maintained in hypoxic aPKC epsilon mitochondria (P < 0.005, n = 8). Electron microscopy revealed a hypoxia-associated increase in mitochondrial number with ultrastructural disarray in WT versus aPKCe hearts. Concordantly, left ventricular work was diminished in hypoxic WT but not aPKC epsilon mice (glucose only perfusions). However, addition of palmitate abrogated this (P < 0.05 vs. WT). aPKC epsilon hearts displayed increased glucose utilization at baseline and with hypoxia. In parallel, p-GSK3 beta and HIF1-alpha peptide levels were increased in hypoxic aPKC epsilon hearts versus WT. Our study demonstrates that modest, sustained PKC epsilon activation blunts cardiac pathophysiologic responses usually observed in response to chronic hypoxia. Moreover, we propose that preferential glucose utilization by PKC epsilon hearts is orchestrated by a p-GSK3 beta/HIF-1 alpha-mediated mechanism, playing a crucial role to sustain contractile function in response to chronic hypobaric hypoxia. J. Cell. Physiol. 226: 2457-2468, 2011. (C) 2010 Wiley-Liss, Inc.