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PKCε promotes cardiac mitochondrial and metabolic adaptation to chronic hypobaric hypoxia by GSK3β inhibition.

ABSTRACT: PKCε is central to cardioprotection. Sub-proteome analysis demonstrated co-localization of activated cardiac PKCε (aPKCε) with metabolic, mitochondrial, and cardioprotective modulators like hypoxia-inducible factor 1α (HIF-1α). aPKCε relocates to the mitochondrion, inactivating glycogen synthase kinase 3β (GSK3β) to modulate glycogen metabolism, hypertrophy and HIF-1α. However, there is no established mechanistic link between PKCε, p-GSK3β and HIF1-α. Here we hypothesized that cardiac-restricted aPKCε improves mitochondrial response to hypobaric hypoxia by altered substrate fuel selection via a GSK3β/HIF-1α-dependent mechanism. aPKCε and wild-type (WT) mice were exposed to 14 days of hypobaric hypoxia (45 kPa, 11% O(2)) and cardiac metabolism, functional parameters, p-GSK3β/HIF-1α 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 aPKCε mitochondria (P < 0.005, n = 8). Electron microscopy revealed a hypoxia-associated increase in mitochondrial number with ultrastructural disarray in WT versus aPKCε hearts. Concordantly, left ventricular work was diminished in hypoxic WT but not aPKCε mice (glucose only perfusions). However, addition of palmitate abrogated this (P < 0.05 vs. WT). aPKCε hearts displayed increased glucose utilization at baseline and with hypoxia. In parallel, p-GSK3β and HIF1-α peptide levels were increased in hypoxic aPKCε hearts versus WT. Our study demonstrates that modest, sustained PKCε activation blunts cardiac pathophysiologic responses usually observed in response to chronic hypoxia. Moreover, we propose that preferential glucose utilization by PKCε hearts is orchestrated by a p-GSK3β/HIF-1α-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

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PKCε promotes cardiac mitochondrial and metabolic adaptation to chronic hypobaric hypoxia by GSK3β inhibition.

McCarthy Joy J Lochner Amanda A Opie Lionel H LH Sack Michael N MN Essop M Faadiel MF

Journal of cellular physiology 20110901 9

PKCε is central to cardioprotection. Sub-proteome analysis demonstrated co-localization of activated cardiac PKCε (aPKCε) with metabolic, mitochondrial, and cardioprotective modulators like hypoxia-inducible factor 1α (HIF-1α). aPKCε relocates to the mitochondrion, inactivating glycogen synthase kinase 3β (GSK3β) to modulate glycogen metabolism, hypertrophy and HIF-1α. However, there is no established mechanistic link between PKCε, p-GSK3β and HIF1-α. Here we hypothesized that cardiac-restricted ...[more]

PMID: 21660969

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Project description:Background and purposeHigh-altitude pulmonary oedema (HAPE) experienced under high-altitude conditions is attributed to mitochondrial redox distress. Hence, hypobaric hypoxia (HH)-induced alteration in expression of mitochondrial biogenesis and dynamics genes was determined in rat lung. Further, such alteration was correlated with expression of mitochondrial DNA (mtDNA)-encoded oxidative phosphorylation (mtOXPHOS) genes. The prophylactic effect of dexamethasone (DEX) in counteracting the HH-induced mitochondrial distress was used as control to understand adaptation to high-altitude exposure.Experimental approachRats pretreated with DEX were exposed to normobaric normoxia (NN) or HH. HH-induced injury was assessed as an increase in lung water content, tissue damage and oxidant generation. Mitochondrial number, mtDNA content and mtOXPHOS activities were measured to determine mitochondrial function. The expression of mitochondrial biogenesis, dynamics and mtOXPHOS genes was studied.Key resultsHH-induced lung injury was associated with decreased mitochondrial number, mtDNA content and mtOXPHOS activities. HH exposure decreased the nuclear gene oestrogen-related receptor-α (ERRα), which interacts with PPAR-γ coactivator-1α (PGC-1α) in controlling mitochondrial metabolism. Consequently, mtOXPHOS transcripts are repressed under HH. Further, HH modulated mitochondrial dynamics by decreasing mitofusin 2 (Mfn2) and augmenting fission 1 (Fis1) and dynamin-related protein 1 (Drp1) expression. Nevertheless, DEX treatment under NN (i.e. adaptation to HH) did not affect mitochondrial biogenesis and dynamics, but increased mtOXPHOS transcripts. Further, mtOXPHOS activities increased together with reduced oxidant generation. Also, DEX pretreatment normalized ERRα along with mitochondrial dynamics genes and increased mtOXPHOS transcripts to elicit the mitochondrial function under HH.Conclusions and implicationsHH stress (HAPE)-mediated mitochondrial dysfunction is due to repressed ERRα and mtOXPHOS transcripts. Thus, ERRα-mediated protection of mitochondrial bioenergetics might be the likely candidate required for lung adaptation to HH.

Project description:Both hypoxia and inhibition of 2-oxoglutarate dehydrogenase complex (OGDHC) are known to change cellular amino acid pools, but the quantitative comparison of the metabolic and physiological outcomes has not been done. We hypothesize that OGDHC inhibition models metabolic changes caused by hypoxia, as both perturb the respiratory chain function, limiting either the NADH (OGDHC inhibition) or oxygen (hypoxia) supply. In the current study, we quantify the changes in the amino acid metabolism after OGDHC inhibition in the highly sensitive to hypoxia cerebellum and compare them to the earlier characterized changes after acute hypobaric hypoxia. In addition, the associated physiological effects are characterized and compared. A specific OGDHC inhibitor succinyl phosphonate (SP) is shown to act similar to hypoxia, increasing levels of many amino acids in the cerebellum of non-pregnant rats, without affecting those in the pregnant rats. Compared with hypoxia, stronger effects of SP in non-pregnant rats are observed on the levels of cerebellar amino acids, electrocardiography (ECG), and freezing time. In pregnant rats, hypoxia affects ECG and behavior more than SP, although none of the stressors significantly change the levels of cerebellar amino acids. The biochemical differences underlying the different physiological actions of SP and hypoxia are revealed by correlation analysis of the studied parameters. The negative correlations of cerebellar amino acids with OGDHC and/or tryptophan, shown to arise after the action of SP and hypoxia, discriminate the overall metabolic action of the stressors. More negative correlations are induced in the non-pregnant rats by hypoxia, and in the pregnant rats by SP. Thus, our findings indicate that the OGDHC inhibition mimics the action of acute hypobaric hypoxia on the cerebellar amino acid levels, but a better prediction of the physiological outcomes requires assessment of integral network changes, such as increases in the negative correlations among the amino acids, OGDHC, and/or tryptophan.

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PKCε promotes cardiac mitochondrial and metabolic adaptation to chronic hypobaric hypoxia by GSK3β inhibition.

Publications

PKCε promotes cardiac mitochondrial and metabolic adaptation to chronic hypobaric hypoxia by GSK3β inhibition.

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