RhoA signaling in cardiomyocytes protects against stress-induced heart failure but facilitates cardiac fibrosis

Abstract

The Ras-related guanosine triphosphatase RhoA mediates pathological cardiac hypertrophy, but also promotes cell survival and is cardioprotective after ischemia/reperfusion injury. To understand how RhoA mediates these opposing roles in the myocardium, we generated mice with a cardiomyocyte-specific deletion of RhoA. Under normal conditions, the hearts from these mice showed functional, structural, and growth parameters similar to control mice. Additionally, the hearts of the cardiomyocyte-specific, RhoA-deficient mice subjected to transverse aortic constriction (TAC)--a procedure that induces pressure overload and, if prolonged, heart failure--exhibited a similar amount of hypertrophy as wild-type mice subjected to TAC. Thus, neither normal cardiac homeostasis nor the initiation of compensatory hypertrophy required RhoA in cardiomyocytes. However, in response to chronic TAC, hearts from mice with cardiomyocyte-specific deletion of RhoA showed greater dilation, with thinner ventricular walls and larger chamber dimensions, and more impaired contractile function than hearts from control mice subjected to chronic TAC. These effects were associated with aberrant calcium signaling, as well as decreased activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and AKT. In addition, hearts from mice with cardiomyocyte-specific RhoA deficiency also showed less fibrosis in response to chronic TAC, with decreased transcriptional activation of genes involved in fibrosis, including myocardin response transcription factor (MRTF) and serum response factor (SRF), suggesting that the fibrotic response to stress in the heart depends on cardiomyocyte-specific RhoA signaling. Our data indicated that RhoA regulates multiple pathways in cardiomyocytes, mediating both cardio-protective (hypertrophy without dilation) and cardio-deleterious effects (fibrosis).

TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis

“…The small GTP-binding protein RhoA plays a central role in cardiac fibrotic signaling in both cardiomyocytes and cardiac fibroblasts20. TAC significantly increased myocardial RhoA activity (Fig.…”

The role of the sphingosine-1-phosphate signaling pathway in osteocyte mechanotransduction

“…The reason for the lower magnitude of Ca 2+ could be due to the application of the inhibitor DMS prior to the shear stress application since in cardiac tissue, S1P 2 could alter Rho A activation and have an impact in subsequent Ca 2+ response [54]. And in cardiomyocytes Rho A affects calcium signaling, as well as ERK and AKT which are parts of the mechanotransduction pathway [55].…”

Phosphodiesterase 5 Inhibition Limits Doxorubicin-induced Heart Failure by Attenuating Protein Kinase G Iα Oxidation

“…One of the well established targets of PKG I␣ is RhoA, a member of the small GTPase family, members of which are known for their ability to regulate growth and survival (30). Indeed, RhoA itself mediates many cell processes including survival (31,32), transmitting signals to end effectors by binding the C terminus of ROCK, which activates it (33). Unfortunately, we failed to develop a co-immunoprecipitation protocol that would allow the interaction of PKG I␣ with RhoA to be assessed in tissue under the various experimental conditions.…”