Research ArticleCardiac Physiology

Combined cardiomyocyte PKCδ and PKCε gene deletion uncovers their central role in restraining developmental and reactive heart growth

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Sci. Signal.  21 Apr 2015:
Vol. 8, Issue 373, pp. ra39
DOI: 10.1126/scisignal.aaa1855

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Abstract

Cell growth is orchestrated by changes in gene expression that respond to developmental and environmental cues. Among the signaling pathways that direct growth are enzymes of the protein kinase C (PKC) family, which are ubiquitous proteins belonging to three distinct subclasses: conventional PKCs, novel PKCs, and atypical PKCs. Functional overlap makes determining the physiological actions of different PKC isoforms difficult. We showed that two novel PKC isoforms, PKCδ and PKCε, redundantly govern stress-reactive and developmental heart growth by modulating the expression of cardiac genes central to stress-activated protein kinase and periostin signaling. Mice with combined postnatal cardiomyocyte-specific genetic ablation of PKCδ and germline deletion of PKCε (DCKO) had normally sized hearts, but their hearts had transcriptional changes typical of pathological hypertrophy. Cardiac hypertrophy and dysfunction induced by hemodynamic overloading were greater in DCKO mice than in mice with a single deletion of either PKCδ or PKCε. Furthermore, gene expression analysis of the hearts of DCKO mice revealed transcriptional derepression of the genes encoding the kinase ERK (extracellular signal–regulated kinase) and periostin. Mice with combined embryonic ablation of PKCδ and PKCε showed enhanced growth and cardiomyocyte hyperplasia that induced pathological ventricular stiffening and early lethality, phenotypes absent in mice with a single deletion of PKCδ or PKCε. Our results indicate that novel PKCs provide retrograde feedback inhibition of growth signaling pathways central to cardiac development and stress adaptation. These growth-suppressing effects of novel PKCs have implications for therapeutic inhibition of PKCs in cancer, heart, and other diseases.

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