Abstract 12839: Cardiac-Specific Deletion of RhoA Results in the Development of Cardiac Hypertrophy via Effects on the Erk/MAPK and PI3K/Akt pathways
Increased cardiac hypertrophy in response to pathological stimuli can, over time, become decompensatory, leading to dilated cardiomyopathy (DCM) and heart failure. Though several hypertrophic signaling pathways in the heart have been identified, the precise mechanisms involved in regulating cardiac pathological vs. physiological response to these processes remains unclear. Recently, a Ras-related small G protein, RhoA, was shown to be a key mediator of in vivo pathological hypertrophy; increased activity of RhoA decreased cardiac contractile function in diabetic animals, and transgenic mice overexpressing wild-type RhoA developed a lethal DCM. Ex vivo, we showed that the DCM phenotype in isolated cardiomyocytes from hearts in end-stage heart failure could be reversed by inhibition of RhoA kinase activity. Based on these findings, we hypothesized that decreased/loss of RhoA activity would be cardioprotective against development of cardiac disease. To test this hypothesis, we generated mice with cardiomyocyte-specific deletion of RhoA (RhoA fl/fl- αMHC-Cre mice). Surprisingly, these mice develop significant cardiac hypertrophy by week 6, with increased heart weight to body weight ratio, cardiomyocyte cell size and reactivation of the hypertrophic fetal gene program, as compared to the wildtype littermate controls. Moreover, 6-8 month old RhoA deleted hearts remain hypertrophic, with no overt fibrosis and no discernable apoptosis present, suggestive of a cardioprotective role, and possible physiological function, for deletion of RhoA in the heart. Biochemical data reveal that both the PI3K/Akt signaling pathway, as well as the mitogen activated protein kinases (MAPK) ERK1/2, p38 and JNK pathways are significantly increased in RhoA deleted hearts, identifying a potential signaling mechanism by which RhoA activity is involved in development of cardiac hypertrophy. Together, these data suggest an interesting, yet highly complex, signaling and regulatory mechanism for RhoA, indicate that deletion of RhoA may be cardioprotective against development of heart failure, and suggest RhoA as a potential target for cardioprotective therapy against cardiac disease development.
- © 2010 by American Heart Association, Inc.