Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2010: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
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Research Abstract |
Transient receptor potential subfamily C(TRPC) 6, receptor-operated Ca2+channels, has been shown to be a positive regulator of calcineurin-NFAT signaling that drives pathologic cardiac remodeling. Cardiac natriuretic peptides, atrial and brain natriuretic peptides(ANP and BNP, respectively) are known to have anti-cardiac hypertrophy effects. Precise molecular mechanisms by which cardiac natriuretic peptides protect hearts against pathological cardiac hypertrophy still remain unclear, In this study to elucidate the molecular pathways, by which cardiac natriuretic peptides negatively regulate pro-hypertrophic signaling, we investigated effects of ANP on TRPC6/calcineurin/NFAT signaling. In HEK293 cells expressing TRPC6, ANP dramatically inhibited TRPC6-mediated Ca2+entry and cationic currents, and in rat neonatal ventricular myocytes(NRVM), ANP significantly inhibited ET-1-induced Ca2+entry and NFAT activation. The inhibitory effect of ANP on TRPC6 was abolished in the presence of specifi
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c PKG inhibitors or by the substitution of alanine for threonine at 69th amino acid of TRPC6, which has been shown to be a PKG phosphorylation site. In model mice lacking a common receptor for atrial and brain natriuretic peptides GC-A (GC-A KO), the expression of TRPC6 and RCAN1 was increased and BTP2 significantly attenuated the cardiac hypertrophy observed in GC-A KO without affecting blood pressure. BTP2 also inhibited AngII-induced cardiac hypertrophy in mice. In cultured neonatal rat ventricular myocytes, overexpression of TRPC6 increased basal and ET-1 induced NFAT-dependent RCAN1 promoter activity. BTP2 significantly and dose-dependently inhibited activation of the RCAN1 promoter, and attenuated hypertrophic response of cultured cardiac myocytes. Knocking-down of TRPC6 and 3 using siRNAs significantly inhibited ET-1. or Ang II. induced increases in Ca2+oscillation, and knocking down either TRPC6 or 3 had a similar effect. TRPC6 and 3 are known to form heteromultimeric cation channels. Pyrazole-3, a selective TRPC3 blocker, which can inhibit the ion channel activity of TRPC3/6 hetero-complex, also inhibited Ang-IIinduced cardiac hypertrophy in mice. All these results suggest that inhibition of TRPC6 is an important component, by which cardiac natriuretic peptides/GC-A/cGMP/PKG pathway protects the hearts from pathological cardiac remodeling, and blockade of TRPC6 could be an novel therapeutic strategy for preventing pathological cardiac remodeling. Less
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