ε Protein Kinase C in Pathological Myocardial Hypertrophy ANALYSIS BY COMBINED TRANSGENIC EXPRESSION OF TRANSLOCATION MODIFIERS AND Gαq

Abstract The e isoform of protein kinase C (PKC) has a critical cardiotrophic function in normal postnatal developing heart as demonstrated by cardiac-specific transgenic expression of ePKC-selective translocation inhibitor (eV1) and activator (ψeRACK) 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 ePKC signaling in pathological myocardial hypertrophy, eV1 or ψeRACK were co-expressed in mouse hearts with Gαq, a PKC-linked hypertrophy signal transducer. Compared with Gαq overexpression alone, co-expression of ψeRACK with Gαq increased ePKC particulate partitioning by 30 ± 2%, whereas co-expression of eV1 with Gαqreduced particulate-associated ePKC by 22 ± 1%. Facilitation of ePKC translocation by ψeRACK in Gαq mice improved cardiac contractile function measured as left ventricular fractional shortening (30 ± 3% Gαq versus 43 ± 2% ψeRACK/Gαq,p < 0.05). Conversely, inhibition of ePKC by eV1 modified the Gαq nonfailing hypertrophy phenotype to that of a lethal dilated cardiomyopathy. These opposing effects of ePKC translocation activation and inhibition in Gαqhypertrophy indicate that ePKC signaling is a compensatory event in myocardial hypertrophy, rather than a pathological event, and support the possible therapeutic efficacy of selective ePKC translocation enhancement in cardiac insufficiency.