{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T03:32:32Z","timestamp":1771471952730,"version":"3.50.1"},"reference-count":47,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,27]],"date-time":"2021-12-27T00:00:00Z","timestamp":1640563200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Japan Agency for Medical Research and Development","award":["15ek0109127h0001"],"award-info":[{"award-number":["15ek0109127h0001"]}]},{"name":"the Ministry of Health, Labour and Welfare, Japan","award":["H26-Intractable diseases-General-076"],"award-info":[{"award-number":["H26-Intractable diseases-General-076"]}]},{"name":"JSPS KAKENHI","award":["17H04181 and 19H03664"],"award-info":[{"award-number":["17H04181 and 19H03664"]}]},{"name":"D.Western Therapeutics Institute","award":["None."],"award-info":[{"award-number":["None."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and right heart failure. Selective pulmonary vasodilators have improved the prognosis of PAH; however, they are not able to reverse pulmonary vascular remodeling. Therefore, a search for new treatment agents is required. H-1337 is an isoquinoline-sulfonamide compound that inhibits multiple serine\/threonine kinases, including Rho-associated protein kinase (ROCK) and mammalian target of rapamycin (mTOR). Here, we investigated the effects of H-1337 on pulmonary hypertension and remodeling in the pulmonary vasculature and right ventricle in experimental PAH induced by SU5416 and hypoxia exposure. H-1337 and H-1337M1 exerted inhibitory effects on ROCK and Akt. H-1337 inhibited the phosphorylation of myosin light chain and mTOR and suppressed the proliferation of smooth muscle cells in vitro. H-1337 treatment also suppressed the phosphorylation of myosin light chain and mTOR in the pulmonary vasculature and decreased right ventricular systolic pressure and the extent of occlusive pulmonary vascular lesions. Furthermore, H-1337 suppressed aggravation of right ventricle hypertrophy. In conclusion, our data demonstrated that inhibition of ROCK and mTOR pathways with H-1337 suppressed the progression of pulmonary vascular remodeling, pulmonary hypertension, and right ventricular remodeling.<\/jats:p>","DOI":"10.3390\/cells11010066","type":"journal-article","created":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T01:18:15Z","timestamp":1640654295000},"page":"66","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416\/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats"],"prefix":"10.3390","volume":"11","author":[{"given":"Hiroki","family":"Shoji","sequence":"first","affiliation":[{"name":"Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan"},{"name":"Department of Respiratory Medicine, Tokyo Rosai Hospital, Tokyo 143-0013, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoko","family":"Yoshida","sequence":"additional","affiliation":[{"name":"D. Western Therapeutics Institute, Inc., Nagoya 460-0003, Japan"},{"name":"Human Research Promotion and Drug Development, Mie University, Mie 514-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5725-1810","authenticated-orcid":false,"given":"Takayuki Jujo","family":"Sanada","sequence":"additional","affiliation":[{"name":"Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Naito","sequence":"additional","affiliation":[{"name":"Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junko","family":"Maruyama","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, School of Medicine, Mie University, Mie 514-8507, Japan"},{"name":"Faculty of Medical Engineering, Suzuka University of Medical Science, Mie 510-0293, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erquan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, School of Medicine, Mie University, Mie 514-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kengo","family":"Sumi","sequence":"additional","affiliation":[{"name":"D. Western Therapeutics Institute, Inc., Nagoya 460-0003, Japan"},{"name":"Human Research Promotion and Drug Development, Mie University, Mie 514-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seiichiro","family":"Sakao","sequence":"additional","affiliation":[{"name":"Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuo","family":"Maruyama","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, School of Medicine, Mie University, Mie 514-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyoshi","family":"Hidaka","sequence":"additional","affiliation":[{"name":"D. Western Therapeutics Institute, Inc., Nagoya 460-0003, Japan"},{"name":"Human Research Promotion and Drug Development, Mie University, Mie 514-8507, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichiro","family":"Tatsumi","sequence":"additional","affiliation":[{"name":"Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1801887","DOI":"10.1183\/13993003.01887-2018","article-title":"Pathology and pathobiology of pulmonary hypertension: State of the art and research perspectives","volume":"53","author":"Humbert","year":"2019","journal-title":"Eur. Respir. 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