PKC? promotes cardiac mitochondrial and metabolic adaptation to chronic hypobaric hypoxia by GSK3? inhibition.

ABSTRACT: PKC? is central to cardioprotection. Sub-proteome analysis demonstrated co-localization of activated cardiac PKC? (aPKC?) with metabolic, mitochondrial, and cardioprotective modulators like hypoxia-inducible factor 1? (HIF-1?). aPKC? relocates to the mitochondrion, inactivating glycogen synthase kinase 3? (GSK3?) to modulate glycogen metabolism, hypertrophy and HIF-1?. However, there is no established mechanistic link between PKC?, p-GSK3? and HIF1-?. Here we hypothesized that cardiac-restricted aPKC? improves mitochondrial response to hypobaric hypoxia by altered substrate fuel selection via a GSK3?/HIF-1?-dependent mechanism. aPKC? 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?/HIF-1? 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? mitochondria (P < 0.005, n = 8). Electron microscopy revealed a hypoxia-associated increase in mitochondrial number with ultrastructural disarray in WT versus aPKC? hearts. Concordantly, left ventricular work was diminished in hypoxic WT but not aPKC? mice (glucose only perfusions). However, addition of palmitate abrogated this (P < 0.05 vs. WT). aPKC? hearts displayed increased glucose utilization at baseline and with hypoxia. In parallel, p-GSK3? and HIF1-? peptide levels were increased in hypoxic aPKC? hearts versus WT. Our study demonstrates that modest, sustained PKC? activation blunts cardiac pathophysiologic responses usually observed in response to chronic hypoxia. Moreover, we propose that preferential glucose utilization by PKC? hearts is orchestrated by a p-GSK3?/HIF-1?-mediated mechanism, playing a crucial role to sustain contractile function in response to chronic hypobaric hypoxia.

SUBMITTER: McCarthy J 

PROVIDER: S-EPMC3411281 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature