Roles of Voltage- and cation-independent TRPC channels in cardiac hypertrophy

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We have reported that angiotensin II or endothelin-1 stimulation induce hypertrophic responses through transient receptor potential canonical channel 3 (TRPC3) and TRPC6-mediated Ca2+ influx using rat neonatal cardiomyocytes. TRPC3/TRPC6 are voltage-independent and cation-non-selective ion channels, and activated by diacylglycerol generated by Gq-stimulated phospholipase C activation. However, these results were obtained from in vitro cell system using receptor stimulation of cardiomyocytes isolated from newborn rats. It is essential to demonstrate the importance of TRPC3/TRPC6 in in vivo hypertrophy model. Therefore, we have examined whether TRPC3/TRPC6 are involved in pressure overload-induced cardiac hypertrophy. Pressure overload is considered as a mouse model of chronic human hypertension, and induces cardiac hypertrophy. As the compound Pyr3 that selectively inhibits TRPC3 was available, we obtained it and administered to pressure overloaded mice. Pressure overload is applied by … More transverse aortic constriction procedure (TAC), and Pyr3 is administered by osmotic mini-pump. Pressure overload-induced hypertrophy was inhibited in Pyr3-treated mice as compare to wild type mice, which was as assessed by increased size of cardiomyocytes and increased expression of ANP. Furthermore, cardiac function such as fractional shortening is improved by the treatment with Pyr3. Next, we also examined the involvement of TRPC6 in pressure overload-induced cardiac hypertrophy. As the function of TRPC6 is inhibited by phosphorylation of TRPC6, we used a cGMP-selective phosphodiesterase (phosphodiesterase type 5:PDE5) inhibitor, sildenafil, for the increase in cardiac cGMP content. The treatment with sildenafil inhibited cardiac hypertrophy by pressure overload. The increased expression of various marker genes of hypertrophy was inhibited by the treatment with sildenafil. In sidenafil-treated mice, anti-phospho-TRPC6 antibody revealed that TRPC6 was phosphorylated at a specific site that is essential for TRPC6-mediated Ca^<2+> influx. These results suggest that TRPC3/TRPC6-mediated Ca^<2+> influx plays an important role in cardiac hypertrophy in vivo as well as in vitro. Less