alpha 1G-dependent T-type Ca2+ current antagonizes cardiac hypertrophy through a NOS3-dependent mechanism in mice

[摘要]：In noncontractile cells, increases in intracellular Ca2+ concentration serve as a second messenger to signal proliferation, differentiation, metabolism, motility, and cell death. Many of these Ca2+-dependent regulatory processes operate in cardiomyocytes, although it remains unclear how Ca2+ serves as a second messenger given the high Ca2+ concentrations that control contraction. T-type Ca2+ channels are reexpressed in adult ventricular myocytes during pathologic hypertrophy, although their physiologic function remains unknown. Here we generated cardiac-specific transgenic mice with inducible expression of alpha 1G, which generates Ca(v)3.1 current, to investigate whether this type of Ca2+ influx mechanism regulates the cardiac hypertrophic response. Unexpectedly, alpha 1G transgenic mice showed no cardiac pathology despite large increases in Ca2+ influx, and they were even partially resistant to pressure overload-, isoproterenol-, and exercise-induced cardiac hypertrophy. Conversely, alpha 1G(-/-) mice displayed enhanced hypertrophic responses following pressure overload or isoproterenol infusion. Enhanced hypertrophy and disease in alpha 1G(-/-) mice was rescued with the alpha 1G transgene, demonstrating a myocyte-autonomous requirement of alpha 1G for protection. Mechanistically, alpha 1G interacted with NOS3, which augmented cGMP-dependent protein kinase type I activity in alpha 1G transgenic hearts after pressure overload. Further, the anti-hypertrophic effect of alpha 1G overexpression was abrogated by a NOS3 inhibitor and by crossing the mice onto the Nos3(-/-) background. Thus, cardiac alpha 1G reexpression and its associated pool of T-type Ca2+ antagonize cardiac hypertrophy through a NOS3-dependent signaling mechanism.

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