title: 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.
  
  
  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.affiliation: Department of Medicine, National Cardiovascular Center, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokudome
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kishimoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Horio
authors.forename: Yuji
authors.initials: Y
authors.lastname: Arai
authors.forename: Daryl O
authors.initials: DO
authors.lastname: Schwenke
authors.forename: Jun
authors.initials: J
authors.lastname: Hino
authors.forename: Ichiro
authors.initials: I
authors.lastname: Okano
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Kawano
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
authors.forename: Mikiya
authors.initials: M
authors.lastname: Miyazato
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism* / Q000502:physiology*; D006332:Cardiomegaly / Q000378:metabolism* / Q000517:prevention & control*; D002478:Cells, Cultured; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D020710:RGS Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D020710:RGS Proteins; C098799:RGS4 protein; D009320:Atrial Natriuretic Factor