Rho kinase signaling and cardiac physiology

Abstract

Rho kinases (ROCKs) are the first discovered RhoA effectors that are now widely known for their effects on actin organization. Recent studies have shown that ROCKs play important roles in cardiac physiology. Abnormal activation of ROCKs participate in multiple cardiovascular pathological processes, including cardiac hypertrophy, apoptosis, fibrosis, systemic hypertension, and pulmonary hypertension. ROCK inhibitors, fasudil and statins, have shown beneficial cardiovascular effects in many animal studies, clinical trials, and applications. Here, we mainly discuss the current understanding of the physiological roles of Rho kinase signaling in the heart, and briefly summarize the roles of ROCKs in cardiac-related vascular dysfunctions. We will also discuss the clinical application of ROCK inhibitors.

Figure 1. Role of Rho kinase signaling in heart failure

RhoA/ROCKs closely participate in the development of multiple pathological changes in heart failure. ROCK1 and ROCK2 are cleaved by caspase-3 and granzyme B, respectively, resulting in active ROCK1 and ROCK2 kinase fragments, which facilitate cardiomyocyte apoptosis. ROCK2 promotes cardiac hypertrophy through 1) increasing the expression of SRF-targeted cardiac fetal genes; and 2) increasing the expression and activity of pro-hypertrophic gene FHOD3. ROCKs also promote cardiac fibrosis through activating MRTF/SRF pathway and YAP/TAZ-TEAD pathway in myofibroblasts. In addition, ROCKs promote pulmonary hypertension through enhancing vasocontraction and inhibiting nitric oxide production. SRF: serum response factor; FHOD3: formin homology 2 domain containing 3; MTRF: myocardin-related transcription factor; YAP: yes-associated protein; TAZ: transcriptional coactivator with PDZ-binding motif; TEAD: transcriptional enhancer factor TEF; RV: right ventricle.