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

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-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.

• Authors: 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
• Journal: Circulation (Circulation) Vol. 117 Issue 18 Pg. 2329-39 (May 06 2008) ISSN: 1524-4539 [Electronic] United States
• PMID: 18443239 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RGS Proteins
• RGS4 protein
• Atrial Natriuretic Factor

Topics

• Animals
• Atrial Natriuretic Factor (metabolism, physiology)
• Cardiomegaly (metabolism, prevention & control)
• Cells, Cultured
• Female
• Male
• Mice
• Mice, Knockout
• Mice, Transgenic
• Myocardium (cytology, metabolism)
• Myocytes, Cardiac (metabolism)
• RGS Proteins (biosynthesis, deficiency, genetics, physiology)
• Signal Transduction (genetics, physiology)