Belumosudil, ROCK2-Specific Inhibitor, alleviates cardiac fibrosis by inhibiting cardiac fibroblasts activation

Cardiac fibrosis is thought to be the hallmark of pathological hypertrophic remodeling, of which the myofibroblasts 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...

Full description

Saved in:
Bibliographic Details
Published in:American journal of physiology. Heart and circulatory physiology 2022-07, Vol.323 (1), p.H235-H247
Main Authors: Liu, Quan, Li, Hua-Yang, Wang, Shun-Jun, Huang, Sui-Qing, Yue, Yuan, Maihemuti, Adilai, Zhang, Yi, Huang, Lin, Luo, Li, Feng, Kang-Ni, Wu, Zhong-Kai
Format: Article
Language:English
Subjects:
Anesthesia
Aorta
Chemical compounds
Enzyme inhibitors
Fibroblasts
Fibrosis
Growth factors
Homology
Hypertrophy
Kinases
Overloading
Pentobarbital
Pharmacology
siRNA
Smad2 protein
Transforming growth factor-b1
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Cardiac fibrosis is thought to be the hallmark of pathological hypertrophic remodeling, of which the myofibroblasts 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 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 week old) under pentobarbital anesthesia. After that, mice were randomly divided into three groups: sham operation + vehicle, TAC + vehicle, TAC + 50 mg·kg ·d 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 Transforming Growth Factor-β1 (TGF-β1)/mothers against decapentaplegic homolog (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.
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00014.2022