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Protein Kinase C&agr; Negatively Regulates Systolic and Diastolic Function in Pathological Hypertrophy

Abstract— The protein kinase C (PKC) family is implicated in cardiac hypertrophy, contractile failure, and &bgr;-adrenergic receptor (&bgr;AR) dysfunction. Herein, we describe the effects of gain- and loss-of-PKC&agr; function using transgenic expression of conventional PKC isoform translocation modifiers. In contrast to previously studied PKC isoforms, activation of PKC&agr; failed to induce cardiac hypertrophy, but instead caused &bgr;AR insensitivity and ventricular dysfunction. PKC&agr; inhibition had opposite effects. Because PKC&agr; is upregulated in human and experimental cardiac hypertrophy and failure, its effects were also assessed in the context of the G&agr;q overexpression model (in which PKC&agr; is transcriptionally upregulated). Normalization (inhibition) of PKC&agr; activity in G&agr;q hearts improved systolic and diastolic function, whereas further activation of PKC&agr; caused a lethal restrictive cardiomyopathy with marked interstitial fibrosis. These results define pathological roles for PKC&agr; as a negative regulator of ventricular systolic and diastolic function.