Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice

J Clin Invest. 2009 Feb;119(2):408-20. doi: 10.1172/JCI35620. Epub 2009 Jan 5.


The heart initially compensates for hypertension-mediated pressure overload by enhancing its contractile force and developing hypertrophy without dilation. Gq protein-coupled receptor pathways become activated and can depress function, leading to cardiac failure. Initial adaptation mechanisms to reduce cardiac damage during such stimulation remain largely unknown. Here we have shown that this initial adaptation requires regulator of G protein signaling 2 (RGS2). Mice lacking RGS2 had a normal basal cardiac phenotype, yet responded rapidly to pressure overload, with increased myocardial Gq signaling, marked cardiac hypertrophy and failure, and early mortality. Swimming exercise, which is not accompanied by Gq activation, induced a normal cardiac response, while Rgs2 deletion in Galphaq-overexpressing hearts exacerbated hypertrophy and dilation. In vascular smooth muscle, RGS2 is activated by cGMP-dependent protein kinase (PKG), suppressing Gq-stimulated vascular contraction. In normal mice, but not Rgs2-/- mice, PKG activation by the chronic inhibition of cGMP-selective phosphodiesterase 5 (PDE5) suppressed maladaptive cardiac hypertrophy, inhibiting Gq-coupled stimuli. Importantly, PKG was similarly activated by PDE5 inhibition in myocardium from both genotypes, but PKG plasma membrane translocation was more transient in Rgs2-/- myocytes than in controls and was unaffected by PDE5 inhibition. Thus, RGS2 is required for early myocardial compensation to pressure overload and mediates the initial antihypertrophic and cardioprotective effects of PDE5 inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomegaly / prevention & control*
  • Cyclic GMP-Dependent Protein Kinase Type I
  • Cyclic GMP-Dependent Protein Kinases / physiology
  • GTP-Binding Protein alpha Subunits, Gq-G11 / physiology
  • Hypertension / complications*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphodiesterase 5 Inhibitors*
  • Phosphodiesterase Inhibitors / pharmacology*
  • Piperazines / pharmacology*
  • Purines / pharmacology
  • RGS Proteins / analysis
  • RGS Proteins / physiology*
  • Sildenafil Citrate
  • Sulfones / pharmacology*


  • Phosphodiesterase 5 Inhibitors
  • Phosphodiesterase Inhibitors
  • Piperazines
  • Purines
  • RGS Proteins
  • Rgs2 protein, mouse
  • Sulfones
  • Sildenafil Citrate
  • Cyclic GMP-Dependent Protein Kinase Type I
  • Cyclic GMP-Dependent Protein Kinases
  • Prkg1 protein, mouse
  • GTP-Binding Protein alpha Subunits, Gq-G11