Regulator of G-protein signaling subtype 4 mediates antihypertrophic effect of locally secreted natriuretic peptides in the heart.

Regulator of G-protein signaling subtype 4 mediates antihypertrophic effect of locally secreted natriuretic peptides in the heart. Research Abstract Details 

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Regulator of G-protein signaling subtype 4 mediates antihypertrophic effect of locally secreted natriuretic peptides in the heart. Abstract Text:

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-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. CONCLUSIONS: 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.

Regulator of G-protein signaling subtype 4 mediates antihypertrophic effect of locally secreted natriuretic peptides in the heart. Publishing Authors By Initials

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Regulator of G-protein signaling subtype 4 mediates antihypertrophic effect of locally secreted natriuretic peptides in the heart. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Circulation

VOLUME: 117

Page Numbers: 2329-39

Journal Abbreviation: Circulation

ISSN: 1524-4539

DAY: 28

MONTH: 04

YEAR: 2008

Regulator of G-protein signaling subtype 4 mediates antihypertrophic effect of locally secreted natriuretic peptides in the heart. Information

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LANGUAGE: eng

NlmUniqueID: 147763

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AFFILIATION: Department of Medicine, National Cardiovascular Center, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan.

Country: United States

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MEDLINETA: Circulation

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