RESUMO
Cardiac fibrosis is thought to be the hallmark of pathological hypertrophic remodeling, of which the myofibroblast transdifferentiation is the key cell biological event. However, there is still no specific and effective therapeutic agent approved for cardiac fibrosis. To investigate the effects of belumosudil, the first ρ-associated kinase-2 (ROCK2)-specific inhibitor, on cardiac hypertrophy, fibrosis, and dysfunction induced by pressure overload, the transverse aortic constriction (TAC) or sham operation was carried out on wild-type C57BL/6 mice (male, 6-8 wk old) under pentobarbital anesthesia. After that, mice were randomly divided into three groups: sham operation + vehicle, TAC + vehicle, TAC + 50 mg·kg-1·day-1 belumosudil. We found that belumosudil effectively ameliorated cardiac hypertrophy, fibrosis, and dysfunction in TAC mice. To elucidate the underlying mechanism, we inhibited the expression of ROCK2 in vitro by either belumosudil or siRNA. We showed that the inhibition of ROCK2 by either belumosudil or knockdown suppressed cardiac fibroblasts activation and proliferation significantly induced by transforming growth factor-ß1 (TGF-ß1). Furthermore, our study confirmed ROCK2 mediates cardiac fibrosis by interacting with TGF-ß1/mothers against decapentaplegic homolog 2 (Smad2) pathway. Taken together, we demonstrated that belumosudil ameliorates cardiac hypertrophy and fibrosis induced by TAC via inhibiting cardiac fibroblasts activation. In conclusion, belumosudil may be a promising therapeutic drug for cardiac hypertrophy and fibrosis induced by myocardial pressure overload.NEW & NOTEWORTHY Although ρ-associated kinase-2 (ROCK2) is the main isoform of ρ-associated kinases (ROCKs) in the heart and more important in cardiac hypertrophy and fibrosis than ρ-associated kinase-1 (ROCK1), there has not been any pharmacological approach to inhibit ROCK2 selectively. Our study demonstrates for the first time that belumosudil, the first ROCK2-specific inhibitor, effectively ameliorates cardiac hypertrophy, fibrosis, and dysfunction induced by TAC via inhibiting cardiac fibroblasts activation.
