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

Sunamura Shinichiro; Satoh Kimio; Kurosawa RyoOhtsuki TomohiroKikuchi NobuhiroElias-Al-Mamun Md.Shimizu ToruIkeda ShoheiSuzuki KotaSatoh TaijyuOmura JunichiNogi MasamichiNumano KazuhikoSiddique Mohammad Abdul HaiMiyata SatoshiMiura MasahitoShimokawa Hiroaki

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

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

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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.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2018年第30期|E7129-E7138|共10页
作者
Sunamura Shinichiro; Satoh Kimio; Kurosawa RyoOhtsuki TomohiroKikuchi NobuhiroElias-Al-Mamun Md.Shimizu ToruIkeda ShoheiSuzuki KotaSatoh TaijyuOmura JunichiNogi MasamichiNumano KazuhikoSiddique Mohammad Abdul HaiMiyata SatoshiMiura MasahitoShimokawa Hiroaki;
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作者单位

Tohoku Univ, Grad Sch Med, Dept Cardiovasc Med, Sendai, Miyagi 9808574, Japan;

Tohoku Univ, Grad Sch Med, Dept Clin Physiol, Hlth Sci, Sendai, Miyagi 9808575, Japan;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
heart failure; oxidative stress; Rho-kinase;

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

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