What is the clinical evidence from this study?

Study design: Other. Population: Cardiac hypertrophy. Intervention: Cardiac RGS4 overexpression vs. Nontransgenic GC-A-KO mice. Primary outcome: Ratio of heart to body weight (p=<0.001).

April 29, 2008Open Access

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

Q: What are the key findings of this study?

Cardiac RGS4 overexpression in GC-A knockout mice significantly reduced the ratio of heart to body weight to 80% of nontransgenic controls (P<0.001), attenuating cardiac hypertrophy.

Key Result

Cardiac RGS4 overexpression in GC-A knockout mice significantly reduced the ratio of heart to body weight to 80% of nontransgenic controls (P<0.001), attenuating cardiac hypertrophy.

Structured PICO

Population

Cultured cardiac myocytes; GC-A knockout (GC-A-KO) mice, wild-type mice, and cardiomyocyte-specific RGS4 transgenic mice crossbred with GC-A-KO mice

Intervention

Atrial natriuretic peptide treatment in vitro; cardiomyocyte-specific RGS4 overexpression in vivo

Comparator

Untreated cells; wild-type mice; nontransgenic GC-A-KO mice

Outcome

Ratio of heart to body weight, cardiomyocyte size, and ventricular calcineurin activitysurrogate

RGS4 mediates the antihypertrophic effects of locally secreted natriuretic peptides in the heart by attenuating Gαq signaling.

Main Result

p-value: p=<0.001

Abstract

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-α to RGS4, PKG-dependent phosphorylation of RGS4, and association of RGS4 and Gα q . In contrast, blockade of GC-A by an antagonist, HS-142-1, attenuated the phosphorylation of RGS4 and association of RGS4 and Gα 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 Hleucine 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 Gα q and its downstream hypertrophic signaling, and that RGS4 plays important roles in GC-A–mediated inhibition of cardiac hypertrophy.