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-β1 (TGF-β1). Furthermore, our study confirmed ROCK2 mediates cardiac
fibrosis by interacting with TGF-β1/
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.