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Umbelliferone improves chronic hypoxia-induced pulmonary hypertension by inhibiting the RhoA/ROCK signaling pathway and autophagy

SHANG Ping¹, SUN Shuai-Bo², LIU Bao-Hua^1,*

¹ Department of Rehabilitation, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China；²Department of Orthopedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China

Abstract

This study aimed to investigate the effects of hypoxia on RhoA/Rho-kinase (ROCK) signaling pathway and autophagy in pulmonary artery smooth muscle cells (PASMCs), and to explore the underlying mechanism of Umbelliferone (Umb) in ameliorating chronic hypoxic pulmonary hypertension. PASMCs were cultured from Sprague-Dawley (SD) rats and randomly divided into control group, hypoxia group, hypoxia + Umb intervention group and normoxia + Umb intervention group. Alpha smooth muscle actin (α-SMA) and LC3 were assessed by immunofluorescence staining. Protein expression of RhoA, ROCK2, p-MYPT1, LC3-II, Beclin-1, p62, C-Caspase 3, Bax and Bcl-2 was analyzed by Western blotting. In in vivo study, SD rats were divided into control group, hypoxia group and hypoxia + Umb intervention group. Weight ratio of the right ventricle (RV)/left ventricle plus septum (LV+S) was detected, and pulmonary arterial morphological features were examined by HE staining. The results indicated that compared with the control group, the LC3-II/LC3-I ratio and expression of Beclin-1 were significantly increased, while p62 expression was significantly decreased, and the expressions of RhoA, ROCK2 and p-MYPT1 were significantly increased in PASMCs of hypoxia group (P < 0.05). The changes of LC3-II/LC3-I ratio, the expressions of Beclin-1, p62, RhoA, ROCK2 and p-MYPT1 in PASMCs were reversed by Umb treatment (P < 0.05). Consistently, the pulmonary arterial wall was thickened and the RV/(LV+S) ratio was increased in hypoxic rats, which were significantly improved by Umb treatment (P < 0.05). These results suggest that Umb can improve hypoxia-induced pulmonary hypertension by inhibiting the RhoA/ROCK signaling pathway and autophagy in PASMCs. 

Key words: pulmonary arterial hypertension; Umbelliferone; autophagy; RhoA

Received: 　　Accepted:

Corresponding author: 刘宝华　　E-mail: bhbh369@sina.com

DOI: 10.13294/j.aps.2022.0056

Citing This Article：

SHANG Ping, SUN Shuai-Bo, LIU Bao-Hua. Umbelliferone improves chronic hypoxia-induced pulmonary hypertension by inhibiting the RhoA/ROCK signaling pathway and autophagy. Acta Physiol Sin 2022; 74 (4): 555-562 (in Chinese with English abstract).