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 3Ј,5Ј-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, [ 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 (PϽ0.001), cardiomyocyte size (PϽ0.01), and ventricular calcineurin activity (PϽ0.05) 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.

Phosphorylation of TRPC6 Channels at Thr69 Is Required for Anti-hypertrophic Effects of Phosphodiesterase 5 Inhibition

“…Knockdown of RGS2 and RGS4 Does Not Affect the Effect of PDE5-IIt has been recently reported that PKG-dependent phosphorylation of RGS2 and RGS4 mediates the anti-hypertrophic effects in mouse hearts (32,40,41). Thus, we next examined the involvement of RGS proteins in the inhibition of agonistinduced Ca 2ϩ responses by PDE5 inhibition, using siRNAs for RGS2 and RGS4.…”

Prevention of PKG1α oxidation augments cardioprotection in the stressed heart

“…We next tested whether membrane-localized PKG1α-targeted proteins were preferentially impacted by PKG1α C42S , focusing on 3 known candidates. Regulator of G protein signaling (RGS) RGS2 and RGS4 bind to and are activated by PKG1α, blunting the hypertrophy and dilation otherwise induced by Gαq activation and mechanical stress (14,15). To test whether reduced PKG1α favored RGS2/4 activation, one or both RGS genes were suppressed by siRNA (Supplemental Figure 12A).…”

Cyclic GMP-Dependent Signaling in Cardiac Myocytes

“…We reported that PKG activation by PDE5 inhibitor fails to de-activate multiple hypertrophy signaling cascades in hearts lacking RGS2, resulting in a lack of the antihypertrophic/remodeling effect, 55 and Tokudome et al reported that RGS4 overexpression ameliorates cardiac spontaneous hypertrophy in NPRA (GCA) null animals. 56 Recent study suggested that PKG-RGS2 is also involved in the ANP-GCA antihypertrophy. 57 Lastly, it is worthwhile mentioning the differential response between the right and left heart to PDE5 inhibitor in hypertrophy/remodeling.…”