Abstract 307: Regulator of G-protein Signaling 2 (RGS2) Suppresses Pathologic but not Physiologic Cardiac Hypertrophy
Regulator of G-protein signaling 2 (RGS2) is a GTPase activating protein thought to negatively regulate Gαq/11-protein coupled signaling. In vitro RGS2 over-expression blunts Gαq/11-stimulated hypertrophy, whereas its knockdown worsens it. Here we tested the impact of pathologic (aortic banding, AB) versus physiologic (swimming, SWM) cardiac stimulation on RGS2-cardiac regulation. Mice lacking RGS2 (RGS2−/−) develop modest hypertension but no baseline cardiac phenotype. RGS2−/− subjected to AB developed accelerated hypertrophy (93% vs 47% increase in heart weight/tibial length at 1 wk, p<0.05) and failure, and early mortality (40% vs. 0% mortality at 1 wk, p=0.012). Their hearts have enhanced activation of Gαq/11-coupled hypertrophic mediators such as calcineurin (Cn), extracellular response kinase 1/2 (ERK1/2), and calmodulin-dependent protein kinase II (CaMK II) compared to controls. In sharp contrast, after 6 weeks of exercise swimming, control and RGS2−/− mice developed similar increases in LV mass (17% and 15% increases in heart weight/tibial length; p<0.001 compared to sedentary controls, NS between genotypes). Both groups also had similar increases in relative wall thickness and LV mass by echocardiography. Invasive pressure-volume loop analysis revealed enhanced cardiac output in swimming mice but no differences between genotypes. The only disparities were that heart rate declined slightly (5%) in controls but was unchanged in RGS2−/−, and RGS2−/− mice swam more slowly (mean velocity 5.0±0.3cm/s vs 6.7±0.3cm/s, by video tracking). Control and RGS2−/− mice ± exercise had negligible changes in the Gαq/11 mediators Cn, ERK1/2, and CaMK II. Thus, RGS2 plays a central role in blunting cardiac hypertrophic signaling and mortality in response to pathological stress, but not to physiological stimulation. This highlights its in vivo specificity to the regulation of Gαq/11 signaling as opposed to the signaling of physiologic hypertrophy.