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Regulator of G-Protein Signaling Subtype 4 Mediates Antihypertrophic Effect of Locally Secreted Natriuretic Peptides in the Heart

2008; Lippincott Williams & Wilkins; Volume: 117; Issue: 18 Linguagem: Inglês

10.1161/circulationaha.107.732990

1524-4539

Takeshi Tokudome, Ichiro Kishimoto, Takeshi Horio, Yuji Arai, Daryl O. Schwenke, Jun Hino, Ichiro Okano, Yuhei Kawano, Masakazu Kohno, Mikiya Miyazato, Kazuwa Nakao, Kenji Kangawa,

Cardiac Fibrosis and Remodeling

Mice lacking guanylyl cyclase-A (GC-A), a natriuretic peptide receptor, have pressure-independent cardiac hypertrophy. However, the mechanism underlying GC-A-mediated inhibition of cardiac hypertrophy remains to be elucidated. In the present report, we examined the role of regulator of G-protein signaling subtype 4 (RGS4), a GTPase activating protein for G(q) and G(i), in the antihypertrophic effects of GC-A.In cultured cardiac myocytes, treatment of atrial natriuretic peptide stimulated the binding of guanosine 3',5'-cyclic monophosphate-dependent protein kinase (PKG) I-alpha to RGS4, PKG-dependent phosphorylation of RGS4, and association of RGS4 and Galpha(q). In contrast, blockade of GC-A by an antagonist, HS-142-1, attenuated the phosphorylation of RGS4 and association of RGS4 and Galpha(q). Moreover, overexpressing a dominant negative form of RGS4 diminished the inhibitory effects of atrial natriuretic peptide on endothelin-1-stimulated inositol 1,4,5-triphosphate production, [(3)H]leucine incorporation, and atrial natriuretic peptide gene expression. Furthermore, expression and phosphorylation of RGS4 were significantly reduced in the hearts of GC-A knockout (GC-A-KO) mice compared with wild-type mice. For further investigation, we constructed cardiomyocyte-specific RGS4 transgenic mice and crossbred them with GC-A-KO mice. The cardiac RGS4 overexpression in GC-A-KO mice significantly reduced the ratio of heart to body weight (P<0.001), cardiomyocyte size (P<0.01), and ventricular calcineurin activity (P<0.05) to 80%, 76%, and 67% of nontransgenic GC-A-KO mice, respectively. It also significantly suppressed the augmented cardiac expression of hypertrophy-related genes in GC-A-KO mice.These results provide evidence that GC-A activates cardiac RGS4, which attenuates Galpha(q) and its downstream hypertrophic signaling, and that RGS4 plays important roles in GC-A-mediated inhibition of cardiac hypertrophy.