![]() The growth of individual myocytes is programmed by neuroendocrine factors that signal through membrane-bound receptors leading to activation of signal-transduction pathways and alterations in gene expression ( 2). Pathologic cardiac hypertrophy, an enlargement of the adult heart caused by disease-inducing stimuli, can cause sudden death and is a leading predictor for the development of heart failure ( 1). Thus, TRPC channels are necessary mediators of pathologic cardiac hypertrophy, in part through a calcineurin–NFAT signaling pathway. Mechanistically, inhibition of TRPC channels in transgenic mice or in cultured neonatal myocytes significantly reduced activity in the calcineurin–nuclear factor of activated T cells (NFAT), a known Ca 2+-dependent hypertrophy-inducing pathway. Moreover, dnTRPC4 inhibited the activity of the TRPC3/6/7 subfamily in the heart, suggesting that these two subfamilies function in coordinated complexes. Importantly, adult myocytes isolated from hypertrophic WT hearts showed a unique Ca 2+ influx activity under store-depleted conditions that was not observed in myocytes from hypertrophied dnTRPC3, dnTRPC6, or dnTRPC4 hearts. dnTRPC transgenic mice also were partially protected from loss of cardiac functional performance following long-term pressure-overload stimulation. Remarkably, all three dn transgenic strategies attenuated the cardiac hypertrophic response following either neuroendocrine agonist infusion or pressure-overload stimulation. ![]() Here we generated cardiac-specific transgenic mice that express dominant-negative (dn) TRPC3, dnTRPC6, or dnTRPC4 toward blocking the activity of the TRPC3/6/7 or TRPC1/4/5 subfamily of channels in the heart. Transient receptor potential canonical (TRPC) channels are important mediators of Ca 2+-dependent signal transduction that can sense stretch or activation of membrane-bound receptors. Pathologic hypertrophy of the heart is regulated through membrane-bound receptors and intracellular signaling pathways that function, in part, by altering Ca 2+ handling and Ca 2+-dependent signaling effectors.
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