Cardiac hypertrophy in humans is frequently associated with a poor prognosis. In cultured rat cardiac myocytes, ligands such as phenylephrine, endothelin-1, angiotensin II, and prostaglandin F2alpha promote a hypertrophic response. There is evidence that the action of these ligands on cultured cells mimics cardiac hypertrophy in humans. Most agonists that cause cultured cardiomyocytes to hypertrophy signal via heterotrimeric G proteins. Regulator of G protein signaling (RGS) proteins are GTPase activating proteins (GAPs) that deactivate asubunits of heterotrimeric G proteins. The main aim of this proposal is to investigate the physiologic role of RGS proteins in the regulation of cardiac hypertrophic growth program. The central hypothesis is that RGS proteins determine the responsiveness of cardiac myocytes to extracellular stimuli, and that RGS gene expression is increased as an adaptive mechanism to limit Gprotein- mediated signal transduction. In the original funding period, we demonstrated that RGS proteins are present in heart, that RGS3 and RGS4 gene expression is responsive to external stimuli, that cardiacspecific overexpression of RGS4 in mice blocks pressure overload- and exercise-induced cardiac hypertrophy, and that RGS4 is a GAP for Gq in the in vivo heart. Despite these findings, many questions remain about the role of RGS proteins in heart disease. In the next phase of this project, we propose to investigate the specific role of RGS2, RGS3, and RGS4, in cardiac myocyte hypertrophy by use of a """"""""knock-down"""""""" strategy in cultured cells. Second, we investigate the specific role of RGS4 in pressure overload- and exercise-induced cardiac hypertrophy by use of mice with both whole-body and cardiacspecific targeted disruption of this gene. Third, we investigate the specific role of RGS3 in pressure overload- and exercise-induced cardiac hypertrophy by use of mice with whole-body targeted disruption of this gene. These experiments will help define the role of RGS proteins in the pathogenesis of cardiac hypertrophy and contractile dysfunction and may provide important information for the development of novel therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL061567-06A1
Application #
6917674
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Buxton, Denis B
Project Start
2000-08-15
Project End
2009-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
6
Fiscal Year
2005
Total Cost
$344,250
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Pang, Paul; Jin, Xiaohua; Proctor, Brandon M et al. (2015) RGS4 inhibits angiotensin II signaling and macrophage localization during renal reperfusion injury independent of vasospasm. Kidney Int 87:771-83
Siedlecki, Andrew M; Jin, Xiaohua; Thomas, Winston et al. (2011) RGS4, a GTPase activator, improves renal function in ischemia-reperfusion injury. Kidney Int 80:263-71
Avery, Joan; Etzion, Sharon; DeBosch, Brian J et al. (2010) TRB3 function in cardiac endoplasmic reticulum stress. Circ Res 106:1516-23
Muslin, Anthony J (2010) A salutary role for calcineurin in the heart. J Mol Cell Cardiol 48:1039-40
Siedlecki, A; Anderson, J R; Jin, X et al. (2010) RGS4 controls renal blood flow and inhibits cyclosporine-mediated nephrotoxicity. Am J Transplant 10:231-41
Etzion, Sharon; Etzion, Yoram; DeBosch, Brian et al. (2010) Akt2 deficiency promotes cardiac induction of Rab4a and myocardial ýý-adrenergic hypersensitivity. J Mol Cell Cardiol 49:931-40
Siedlecki, Andrew M; Jin, Xiaohua; Muslin, Anthony J (2009) Uremic cardiac hypertrophy is reversed by rapamycin but not by lowering of blood pressure. Kidney Int 75:800-8
Proctor, Brandon M; Jin, Xiaohua; Lupu, Traian S et al. (2008) Requirement for p38 mitogen-activated protein kinase activity in neointima formation after vascular injury. Circulation 118:658-66
Muslin, Anthony J (2008) MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets. Clin Sci (Lond) 115:203-18
DeBosch, Brian J; Muslin, Anthony J (2008) Insulin signaling pathways and cardiac growth. J Mol Cell Cardiol 44:855-64

Showing the most recent 10 out of 20 publications