Fasudil preserves lung endothelial function and reduces pulmonary vascular remodeling in a rat model of end‑stage pulmonary hypertension with left heart disease

Zhuang,Rulin; Wu,Jinfu; Lin,Fang; Han,Lu; Liang,Xiaoting; Meng,Qingshu; Jiang,Yuyu; Wang,Zhulin; Yue,Aixue; Gu,Yuying; Fan,Huimin; Zhou,Xiaohui; Liu,Zhongmin

doi:10.3892/ijmm.2018.3728

Fasudil preserves lung endothelial function and reduces pulmonary vascular remodeling in a rat model of end‑stage pulmonary hypertension with left heart disease

Authors:
- Rulin Zhuang
- Jinfu Wu
- Fang Lin
- Lu Han
- Xiaoting Liang
- Qingshu Meng
- Yuyu Jiang
- Zhulin Wang
- Aixue Yue
- Yuying Gu
- Huimin Fan
- Xiaohui Zhou
- Zhongmin Liu
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Affiliations: Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China, Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China, Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China
Published online on: June 13, 2018 https://doi.org/10.3892/ijmm.2018.3728
Pages: 1341-1352
Copyright: © Zhuang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pulmonary hypertension (PH) due to left heart disease (LHD) is a common condition associated with significant morbidity. It contributes to the elevation of pulmonary vascular resistance and mean pulmonary pressure, eventually leading to heart failure and even mortality. The present study aimed to explore the potential efficacy of late and long‑term treatment with a Rho‑kinase (ROCK) signaling inhibitor, namely fasudil, in a rat model of end‑stage PH‑LHD. The PH‑LHD model was established by supracoronary aortic banding, and the effect of fasudil treatment on the progression of PH‑LHD was monitored. After 9 weeks (63 days) of supracoronary aortic banding, a significant increase in mean pulmonary pressure and RV systolic pressure was observed in the rats, associated with increased RhoA/ROCK activity in the lungs. Therapy with fasudil (30 mg/kg/day, intraperitoneal) for 4 weeks from postoperative day 35 reversed the hemodynamic disorder and prevented pulmonary vascular remodeling in rats with PH‑LHD. In addition, the blockade of ROCK signaling by fasudil decreased the protein levels of endothelin‑1 (ET‑1) and the mRNA expression levels of endothelin A receptor and promoted the production of nitric oxide (NO) in rats with PH‑LHD. Furthermore, fasudil inhibited the migration of human pulmonary microvascular endothelial cells and the proliferation of pulmonary artery smooth muscle cells induced by ET‑1. Therefore, this late, long‑term blockade of the ROCK pathway by fasudil may be a promising strategy to reverse hemodynamic dysfunction and impede the development of end‑stage PH‑LHD in patients.

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