A G13-Mediated Signaling Pathway is Required for Pressure Overload-Induced Cardiac Remodeling and Heart Failure
Background—Cardiac remodeling in response to pressure or volume overload plays an important role in the pathogenesis of heart failure. Various mechanisms have been suggested to translate mechanical stress into structural changes, one of them being the release of humoral factors such as angiotensin II or endothelin-1, which in turn promote cardiac hypertrophy and fibrosis. A large body of evidence suggests that the pro-hypertrophic effects of these factors are mediated by receptors coupled to the Gq/11 family of heterotrimeric G-proteins. Most Gq/11-coupled receptors, however, can also activate G-proteins of the G12/13 family, but the role G12/13 in cardiac remodeling is not understood.
Methods and Results—We use in this study siRNA-mediated knockdown in vitro as well as conditional gene inactivation in vivo to study the role of the G12/13 family in pressure overload-induced cardiac remodeling. In detail, we show that inducible, cardiomyocyte-specific inactivation of the α-subunit of G13, Gα13, does not affect basal heart function, but protects mice from pressure overload-induced hypertrophy and fibrosis equally efficient as inactivation of Gαq/11. Furthermore, inactivation of Gα13 prevents development of heart failure up to one year after overloading. On the molecular level we show that Gα13, but not Gαq/11, controls agonist-induced expression of hypertrophy-specific genes through activation of the small GTPase RhoA and consecutive activation of myocardin-related transcription factors (MRTF).
Conclusions—Our data show that the G12/13 family of heterotrimeric G-proteins is centrally involved in pressure overload-induced cardiac remodeling and plays a central role in the transition to heart failure.
- Received April 2, 2012.
- Accepted September 6, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited