Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice

Shinichiro Sunamura, Kimio Satoh, Ryo Kurosawa, Tomohiro Ohtsuki, Nobuhiro Kikuchi, Elias-Al-Mamun, Toru Shimizu, Shohei Ikeda, Kota Suzuki, Taijyu Satoh, Junichi Omura, Masamichi Nogi, Kazuhiko Numano, Mohammad Abdul Hai Siddique, Satoshi Miyata, Masahito Miura, Hiroaki Shimokawa

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

Although postcapillary pulmonary hypertension (PH) is an important prognostic factor for patients with heart failure (HF), its pathogenesis remains to be fully elucidated. To elucidate the different roles of Rho-kinase isoforms, ROCK1 and ROCK2, in cardiomyocytes in response to chronic pressure overload, we performed transverse aortic constriction (TAC) in cardiac-specific ROCK1-deficient (cROCK1/) and ROCK2-deficient (cROCK2/) mice. Cardiomyocyte-specific ROCK1 deficiency promoted pressure-overload-induced cardiac dysfunction and postcapillary PH, whereas cardiomyocyte-specific ROCK2 deficiency showed opposite results. Histological analysis showed that pressure-overload-induced cardiac hypertrophy and fibrosis were enhanced in cROCK1/ mice compared with controls, whereas cardiac hypertrophy was attenuated in cROCK2/ mice after TAC. Consistently, the levels of oxidative stress were up-regulated in cROCK1/ hearts and down-regulated in cROCK2/ hearts compared with controls after TAC. Furthermore, cyclophilin A (CyPA) and basigin (Bsg), both of which augment oxidative stress, enhanced cardiac dysfunction and postcapillary PH in cROCK1/ mice, whereas their expressions were significantly lower in cROCK2/ mice. In clinical studies, plasma levels of CyPA were significantly increased in HF patients and were higher in patients with postcapillary PH compared with those without it. Finally, high-throughput screening demonstrated that celastrol, an antioxidant and antiinflammatory agent, reduced the expressions of CyPA and Bsg in the heart and the lung, ameliorating cardiac dysfunction and postcapillary PH induced by TAC. Thus, by differentially affecting CyPA and Bsg expressions, ROCK1 protects and ROCK2 jeopardizes the heart from pressure-overload HF with postcapillary PH, for which celastrol may be a promising agent.

Original languageEnglish
Pages (from-to)E7129-E7138
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number30
DOIs
Publication statusPublished - 2018 Jul 24

Keywords

  • Heart failure
  • Rho-kinase
  • oxidative stress

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice'. Together they form a unique fingerprint.

Cite this