ε Protein kinase C in pathological myocardial hypertrophy -: Analysis by combined transgenic expression of translocation modifiers and Gαq

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 epsilon PKC-selective translocation inhibitor (epsilon V1) and activator (psi epsilon RACK) 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 epsilon PKC signaling in pathological myocardial hypertrophy, epsilon V1 or psi epsilon RACK were coexpressed in mouse hearts with G alpha(q), a PKC-linked hypertrophy signal transducer. Compared with G alpha(q) overexpression alone, co-expression of psi epsilon RACK with G alpha(q) increased epsilon PKC particulate partitioning by 30 +/- 2%, whereas co-expression of epsilon V1 with G alpha(q) reduced particulate-associated epsilon PKC by 22 +/- 1%. Facilitation of epsilon PKC translocation by psi epsilon RACK in G alpha(q) mice improved cardiac contractile function measured as left ventricular fractional shortening (30 +/- 3% G alpha(q) versus 43 +/- 2% psi epsilon RACK/ G alpha(q), p < 0.05). Conversely, inhibition of epsilon PKC by epsilon V1 modified the G alpha(q) nonfailing hypertrophy phenotype to that of a lethal dilated cardiomyopathy. These opposing effects of epsilon PKC translocation activation and inhibition in G alpha(q) -hypertrophy indicate that epsilon PKC signaling is a compensatory event in myocardial hypertrophy, rather than a pathological event, and support the possible therapeutic efficacy of selective epsilon PKC translocation enhancement in cardiac insufficiency.