title: Epsilon protein kinase C in pathological myocardial hypertrophy. Analysis by combined transgenic expression of translocation modifiers and Galphaq.
abstract: The epsilon isoform of protein kinase C (PKC) has a critical cardiotrophic function in normal postnatal developing heart as demonstrated by cardiac-specific transgenic expression of epsilonPKC-selective translocation inhibitor (epsilonV1) and activator (psiepsilonRACK) peptides (Mochly-Rosen, D., Wu, G., Hahn, H., Osinska, H., Liron, T., Lorenz, J. N., Robbins, J., and Dorn, G. W., II (2000) Circ. Res. 86, 1173-1179). To define the role of epsilonPKC signaling in pathological myocardial hypertrophy, epsilonV1 or psiepsilonRACK were co-expressed in mouse hearts with Galpha(q), a PKC-linked hypertrophy signal transducer. Compared with Galpha(q) overexpression alone, co-expression of psiepsilonRACK with Galpha(q) increased epsilonPKC particulate partitioning by 30 +/- 2%, whereas co-expression of epsilonV1 with Galpha(q) reduced particulate-associated epsilonPKC by 22 +/- 1%. Facilitation of epsilonPKC translocation by psiepsilonRACK in Galpha(q) mice improved cardiac contractile function measured as left ventricular fractional shortening (30 +/- 3% Galpha(q) versus 43 +/- 2% psiepsilonRACK/Galpha(q), p < 0.05). Conversely, inhibition of epsilonPKC by epsilonV1 modified the Galpha(q) nonfailing hypertrophy phenotype to that of a lethal dilated cardiomyopathy. These opposing effects of epsilonPKC translocation activation and inhibition in Galpha(q) hypertrophy indicate that epsilonPKC signaling is a compensatory event in myocardial hypertrophy, rather than a pathological event, and support the possible therapeutic efficacy of selective epsilonPKC translocation enhancement in cardiac insufficiency.
authors.affiliation: Division of Cardiology, University of Cincinnati, Cincinnati, Ohio 45267, USA.
authors.forename: G
authors.initials: G
authors.lastname: Wu
authors.forename: T
authors.initials: T
authors.lastname: Toyokawa
authors.forename: H
authors.initials: H
authors.lastname: Hahn
authors.forename: G W
authors.initials: GW
authors.lastname: Dorn
mesh_terms: D000818:Animals; D001692:Biological Transport; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D018390:Gene Targeting; D006334:Heart Function Tests; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009842:Oligopeptides / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D015398:Signal Transduction; D014018:Tissue Distribution
chemical_list: D007527:Isoenzymes; D009842:Oligopeptides; D010446:Peptide Fragments; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins