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(Circulation. 2008;117:2329-2339.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

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

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

From the Research Institute (T.T., Y.A., D.O.S., J.H., I.O., M.M., K.K.) and Department of Medicine (I.K., T.H., Y.K.), National Cardiovascular Center, Suita, Osaka, Japan; Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Faculty of Medicine, Kagawa, Japan (M.K.); and Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan (K.N.).

Correspondence to Ichiro Kishimoto, MD, PhD, Department of Medicine, National Cardiovascular Center, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail kishimot{at}ri.ncvc.go.jp

Received August 9, 2007; accepted March 5, 2008.

Background— 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.

Methods and Results— In cultured cardiac myocytes, treatment of atrial natriuretic peptide stimulated the binding of guanosine 3',5'-cyclic monophosphate-dependent protein kinase (PKG) I- to RGS4, PKG-dependent phosphorylation of RGS4, and association of RGS4 and G_q. In contrast, blockade of GC-A by an antagonist, HS-142-1, attenuated the phosphorylation of RGS4 and association of RGS4 and G_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, [³H]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.

Conclusions— These results provide evidence that GC-A activates cardiac RGS4, which attenuates G_q and its downstream hypertrophic signaling, and that RGS4 plays important roles in GC-A–mediated inhibition of cardiac hypertrophy.

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CLINICAL PERSPECTIVE

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Clinical Summaries
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