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 language | English (US) |
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Pages (from-to) | 1173-1179 |
Number of pages | 7 |
Journal | Circulation research |
Volume | 86 |
Issue number | 11 |
DOIs | |
State | Published - Jun 9 2000 |
Externally published | Yes |
Keywords
- Cardiac hypertrophy
- Cardiomyopathy
- Protein kinase C
- Transgenic mouse
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine