Abstract P189: RhoA Functions as an Antihypertrophic Switch in the Mouse Heart
Background. Small GTPase RhoA has been previously implicated as an important signaling effector within the cardiomyocyte. However, recent studies have challenged the hypothesized role of RhoA as an effector of cardiac hypertrophy. Therefore, this study examined the in vivo role of RhoA in the development of pathological cardiac hypertrophy.
Methods and results. Endogenous RhoA protein expression and activity levels (GTP-bound) in wild-type hearts were significantly increased after pressure overload induced by transverse aortic constriction (TAC). To investigate the necessity of RhoA within the adult heart, RhoA-LoxP-targeted (RhoAflx/flx) mice were crossed with transgenic mice expressing Cre recombinase under the control of the endogenous cardiomyocyte-specific β-myosin heavy chain (β-MHC) promoter to generate RhoAβMHC-cre mice. Deletion of RhoA with β-MHC-Cre produced viable adults with > 85% loss of RhoA protein in the heart, without altering the basic architecture and function of the heart compared to control hearts, at both 2 and 8 months of age. However, subjecting RhoAβMHC-cre hearts to 2 weeks of TAC resulted in marked increase in cardiac hypertrophy (HW/BW (mg/g): 9.5 ± 0.3 for RhoAβMHC-cre versus 7.7 ± 0.4 for RhoAflx/flx; and cardiomyocyte size (mm2): 407 ± 21 for RhoAβMHC-cre versus 262 ± 8 for RhoAflx/flx; n ≥ 8 per group; p<0.01) and a significantly increased fibrotic response. Moreover, RhoAβMHC-cre hearts transitioned more quickly into heart failure whereas control mice maintained proper cardiac function (fractional shortening (%): 23.3 ± 1.2 for RhoAβMHC-cre versus 29.3 ± 1.2 for RhoAflx/flx; n ≥ 8 per group; p<0.01; 12 weeks after TAC). The latter was further associated with a significant increase in lung weight normalized to body weight and re-expression of the cardiac fetal gene program. In addition, these mice also displayed greater cardiac hypertrophy in response to 2 weeks of angiotensinII/phenylephrine infusion.
Conclusion. These data identify RhoA as an antihypertrophic molecular switch in the mouse heart.
- © 2011 by American Heart Association, Inc.