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Differential and conditional activation of PKC-isoforms dictates cardiac adaptation during physiological to pathological hypertrophy.

ABSTRACT: A cardiac hypertrophy is defined as an increase in heart mass which may either be beneficial (physiological hypertrophy) or detrimental (pathological hypertrophy). This study was undertaken to establish the role of different protein kinase-C (PKC) isoforms in the regulation of cardiac adaptation during two types of cardiac hypertrophy. Phosphorylation of specific PKC-isoforms and expression of their downstream proteins were studied during physiological and pathological hypertrophy in 24 week male Balb/c mice (Mus musculus) models, by reverse transcriptase-PCR, western blot analysis and M-mode echocardiography for cardiac function analysis. PKC-? was significantly induced during pathological hypertrophy while PKC-? was exclusively activated during physiological hypertrophy in our study. PKC-? activation during pathological hypertrophy resulted in cardiomyocyte apoptosis leading to compromised cardiac function and on the other hand, activation of PKC-? during physiological hypertrophy promoted cardiomyocyte growth but down regulated cellular apoptotic load resulting in improved cardiac function. Reversal in PKC-isoform with induced activation of PKC-? and simultaneous inhibition of phospho-PKC-? resulted in an efficient myocardium to deteriorate considerably resulting in compromised cardiac function during physiological hypertrophy via augmentation of apoptotic and fibrotic load. This is the first report where PKC-? and -? have been shown to play crucial role in cardiac adaptation during physiological and pathological hypertrophy respectively thereby rendering compromised cardiac function to an otherwise efficient heart by conditional reversal of their activation.

SUBMITTER: Naskar S

PROVIDER: S-EPMC4130596 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Differential and conditional activation of PKC-isoforms dictates cardiac adaptation during physiological to pathological hypertrophy.

Naskar Shaon S Datta Kaberi K Mitra Arkadeep A Pathak Kanchan K Datta Ritwik R Bansal Trisha T Sarkar Sagartirtha S

PloS one 20140812 8

A cardiac hypertrophy is defined as an increase in heart mass which may either be beneficial (physiological hypertrophy) or detrimental (pathological hypertrophy). This study was undertaken to establish the role of different protein kinase-C (PKC) isoforms in the regulation of cardiac adaptation during two types of cardiac hypertrophy. Phosphorylation of specific PKC-isoforms and expression of their downstream proteins were studied during physiological and pathological hypertrophy in 24 week mal ...[more]

PMID: 25116170

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Project description:Compelling evidence suggests that mitochondrial dysfunction contributes to the pathogenesis of heart failure, including defects in the substrate oxidation, and the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS). However, whether such changes occur early in the development of heart failure, and are potentially involved in the pathologic events that lead to cardiac dysfunction is unknown. To address this question, we conducted transcriptomic/metabolomics profiling in hearts of mice with two progressive stages of pressure overload-induced cardiac hypetrophy: i) cardiac hypertrophy with preserved ventricular function achieved via transverse aortic constriction for 4 weeks (TAC) and ii) decompensated cardiac hypertrophy or heart failure (HF) caused by combining 4 wk TAC with a small apical myocardial infarction. Transcriptomic analyses revealed, as shown previously, downregulated expression of genes involved in mitochondrial fatty acid oxidation in both TAC and HF hearts compared to sham-operated control hearts. Surprisingly, however, there were very few changes in expression of genes involved in other mitochondrial energy transduction pathways, ETC, or OXPHOS. Metabolomic analyses demonstrated significant alterations in pathway metabolite levels in HF (but not in TAC), including elevations in acylcarnitines, a subset of amino acids, and the lactate/pyruvate ratio. In contrast, the majority of organic acids were lower than controls. This metabolite profile suggests “bottlenecks” in the carbon substrate input to the TCA cycle. This transcriptomic/metabolomic profile was markedly different from that of mice PGC-1a/b deficiency in which a global downregulation of genes involved in mitochondrial ETC and OXPHOS was noted. In addition, the transcriptomic/metabolomic signatures of HF differed markedly from that of the exercise-trained mouse heart. We conclude that in contrast to current dogma, alterations in mitochondrial metabolism that occur early in the development of heart failure reflect largely post-transcriptional mechanisms resulting in impedance to substrate flux into the TCA cycle, reflected by alterations in the metabolome. Microarray gene expression profiling was performed with bi-ventricle RNA isolated from (1) 3 month-old female C57Bl6/J mice with transverse aortic constriction (CH), vs sham-operated control (Sham-CH), (2) 3 month-old female C57Bl6/J mice with heart failure (HF), vs. sham-operated control (Sham-HF); (3) 2 month-old female C57Bl6/J mice with voluntary wheel training for 2 months (Run), vs. Sedentary control (Sed). Five biological replicates are included for each group.

Dataset Information

Differential and conditional activation of PKC-isoforms dictates cardiac adaptation during physiological to pathological hypertrophy.

Publications

Differential and conditional activation of PKC-isoforms dictates cardiac adaptation during physiological to pathological hypertrophy.

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