Cardiotrophic effects of protein kinase C ε: Analysis by in vivo modulation of PKCε translocation

Daria Mochly-Rosen, Guangyu Wu, Harvey Hahn, Hanna Osinska, Tamar Liron, John N. Lorenz, Atsuko Yatani, Jeffrey Robbins, Gerald W. Dorn

Research output: Contribution to journalArticlepeer-review

173 Scopus citations

Abstract

Protein kinase C (PKC) is a key mediator of many diverse physiological and pathological responses. Although little is known about the specific in vivo roles of the various cardiac PKC isozymes, activation-induced translocation of PKC is believed to be the primary determinant of isozyme- specific functions. Recently, we have identified a catalytically inactive peptide translocation inhibitor (εV1) and translocation activator (ψεRACK [receptors for activated C kinase]) specifically targeting PKCε. Using cardiomyocyte-specific transgenic expression of these peptides, We combined loss- and gain-of-function approaches to elucidate the in vivo consequences of myocardial PKCε signaling. As expected for a PKCε RACK binding peptide, confocal microscopy showed that εV1 decorated cross-striated elements and intercalated disks of cardiac myocytes. Inhibition of cardiomyocyte PKCε by εV1 at lower expression levels upregulated α-skeletal actin gene expression, increased cardiomyocyte cell size, and modestly impaired left ventricular fractional shortening. At high expression levels, εV1 caused a lethal dilated cardiomyopathy. In contrast, enhancement of PKCε translocation with ψεRACK resulted in selectively increased β myosin heavy chain gene expression and normally functioning concentric ventricular remodeling with decreased cardiomyocyte size. These results identify for the first time a role for PKCε signaling in normal postnatal maturational myocardial development and suggest the potential for PKCε activators to stimulate 'physiological' cardiomyocyte growth.

Original languageEnglish
Pages (from-to)1173-1179
Number of pages7
JournalCirculation research
Volume86
Issue number11
DOIs
StatePublished - Jun 9 2000
Externally publishedYes

Keywords

  • Cardiac hypertrophy
  • Cardiomyopathy
  • Protein kinase C
  • Transgenic mouse

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