In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 118, No. suppl_18 ( 2008-10-28)
Abstract:
Regulator of G-protein signaling 2 (RGS2) is a GTPase activating protein thought to negatively regulate Gα q/11 -protein coupled signaling. In vitro RGS2 over-expression blunts Gα q/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 Gα q/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 Gα q/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 Gα q/11 signaling as opposed to the signaling of physiologic hypertrophy. Changes in Heart Weight/Tibial Length in response to Aortic Banding (AB) vs Swimming (SWM)
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.118.suppl_18.S_281-d
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2008
detail.hit.zdb_id:
1466401-X
