The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats
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 agen...
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MDPI AG
2021-12-01
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| author | Hiroki Shoji Yoko Yoshida Takayuki Jujo Sanada Akira Naito Junko Maruyama Erquan Zhang Kengo Sumi Seiichiro Sakao Kazuo Maruyama Hiroyoshi Hidaka Koichiro Tatsumi |
| author_facet | Hiroki Shoji Yoko Yoshida Takayuki Jujo Sanada Akira Naito Junko Maruyama Erquan Zhang Kengo Sumi Seiichiro Sakao Kazuo Maruyama Hiroyoshi Hidaka Koichiro Tatsumi |
| author_sort | Hiroki Shoji |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T03:46:44Z |
| format | Article |
| id | doaj.art-c606b099d8604ba3880cb1ddc26466da |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T03:46:44Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-c606b099d8604ba3880cb1ddc26466da2023-11-23T11:19:40ZengMDPI AGCells2073-44092021-12-011116610.3390/cells11010066The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in RatsHiroki Shoji0Yoko Yoshida1Takayuki Jujo Sanada2Akira Naito3Junko Maruyama4Erquan Zhang5Kengo Sumi6Seiichiro Sakao7Kazuo Maruyama8Hiroyoshi Hidaka9Koichiro Tatsumi10Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, JapanD. Western Therapeutics Institute, Inc., Nagoya 460-0003, JapanDepartment of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, JapanDepartment of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, JapanDepartment of Anesthesiology and Critical Care Medicine, School of Medicine, Mie University, Mie 514-8507, JapanDepartment of Anesthesiology and Critical Care Medicine, School of Medicine, Mie University, Mie 514-8507, JapanD. Western Therapeutics Institute, Inc., Nagoya 460-0003, JapanDepartment of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, JapanDepartment of Anesthesiology and Critical Care Medicine, School of Medicine, Mie University, Mie 514-8507, JapanD. Western Therapeutics Institute, Inc., Nagoya 460-0003, JapanDepartment of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, JapanPulmonary 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.https://www.mdpi.com/2073-4409/11/1/66pulmonary hypertensionRho-associated protein kinase signalingmammalian target of rapamycin signalinganimal model of pulmonary arterial hypertensionright ventricular remodeling |
| spellingShingle | Hiroki Shoji Yoko Yoshida Takayuki Jujo Sanada Akira Naito Junko Maruyama Erquan Zhang Kengo Sumi Seiichiro Sakao Kazuo Maruyama Hiroyoshi Hidaka Koichiro Tatsumi The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats Cells pulmonary hypertension Rho-associated protein kinase signaling mammalian target of rapamycin signaling animal model of pulmonary arterial hypertension right ventricular remodeling |
| title | The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats |
| title_full | The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats |
| title_fullStr | The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats |
| title_full_unstemmed | The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats |
| title_short | The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats |
| title_sort | isoquinoline sulfonamide compound h 1337 attenuates su5416 hypoxia induced pulmonary arterial hypertension in rats |
| topic | pulmonary hypertension Rho-associated protein kinase signaling mammalian target of rapamycin signaling animal model of pulmonary arterial hypertension right ventricular remodeling |
| url | https://www.mdpi.com/2073-4409/11/1/66 |
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