Molecular changes in the early phase of renin-dependent cardiac hypertrophy in hypertensive cyp1a1ren-2 transgenic rats.

An early response to high arterial pressure is the development of cardiac hypertrophy. Functional and transcriptional regulation of ion channels and Ca2+ handling proteins are involved in this process but the relative contribution of each is unclear. In this study, we investigated the expression of genes involved in action potential generation and Ca2+ homeostasis of cardiomyocytes in hypertensive cyp1a1ren-2 transgenic rats. In this model, the transgene prorenin was induced by indole-3-carbinol for 2 weeks allowing the induction of hypertension. Electrophysiological recordings from cardiomyocytes of hypertensive rats revealed a slight increase in membrane capacitance consistent with cellular hypertrophy. L-type calcium current density was reduced by 30%. Left ventricles of hypertensive rats showed a significant increase in transcript and protein levels of the cation channel TRPC6 and FK506-binding protein, whereas levels of SERCA2 and voltage-dependent potassium channels K(v)4.2 and K(v)4.3 were found to be decreased. Further, a marked nuclear localization of the transcription factors GATA4 and NFATC4 was observed in cardiac tissue of hypertensive rats. The cyp1a1ren-2 transgenic rat thus appears to be a valid model to investigate early changes in cardiac hypertrophy. This study points to roles for TRPC6, FK506BP, SERCA2, K(v)4.2, and K(v)4.3 in the development of cardiac hypertrophy.