Salusin-β, a TOR2A gene product, promotes proliferation, migration, fibrosis, and calcification of smooth muscle cells and accelerates the imbalance of vasomotor function and vascular remodeling in monocrotaline-induced pulmonary hypertensive rats

Xingxing Wang; Aidong Chen; Ruihua Hu; Feng Zhang; Shuxin Liang; Changlei Bao; Xuanxuan Liu; Haiyang Tang; Ying Han

doi:10.3389/fphar.2022.928834

Salusin-β, a TOR2A gene product, promotes proliferation, migration, fibrosis, and calcification of smooth muscle cells and accelerates the imbalance of vasomotor function and vascular remodeling in monocrotaline-induced pulmonary hypertensive rats

Front Pharmacol. 2022 Sep 30:13:928834. doi: 10.3389/fphar.2022.928834. eCollection 2022.

Authors

Xingxing Wang¹, Aidong Chen¹, Ruihua Hu¹, Feng Zhang¹, Shuxin Liang², Changlei Bao^{2

3}, Xuanxuan Liu⁴, Haiyang Tang², Ying Han¹

Affiliations

¹ Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, and Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.
² State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
³ College of Veterinary Medicine, Northwest A&F University, Yangling, China.
⁴ Department of Physiology, Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, China.

Abstract

Purpose: The hyper-proliferation, promoted migration, fibrosis, and calcification of pulmonary arterial smooth muscle cells (PASMCs) play critical roles in pulmonary artery (PA) continuous contraction and vascular remodeling, leading to elevated pulmonary arterial resistance and pulmonary hypertension (PH). In this study, we sought to ascertain the effects of a TOR2A gene product, salusin-β, on PASMCs' proliferation, migration, fibrosis, calcification, and the imbalance of vasomotor function as well as pulmonary vascular remodeling in monocrotaline (MCT)-induced PH rats and their underlying mechanisms. Methods: Knockdown or overexpression of salusin-β in rats or PASMCs was performed through tail vein injection or cell transfection of virus. The right ventricular systolic pressure (RVSP) of the rat was measured by right ventricle catheterization. Sodium nitroprusside (SNP) or acetylcholine (ACh)-induced dose-dependent relaxation was used to evaluate the vasodilatation function. Primary PASMCs were isolated from the PAs of control and PH rats. Results: The salusin-β protein expressions were significantly increased in PAs and PASMCs isolated from PH rats compared with control rats. Knockdown of salusin-β in rats decreased high K⁺ solution-induced contraction, RVSP and RV hypertrophy index, improved SNP or ACh-induced vascular relaxation of PAs, and relieved vascular remodeling and calcification of PAs from PH rats. Silencing salusin-β in PASMCs isolated from PH rats alleviated the proliferation, migration, fibrosis, and calcification, as well as the NAD(P)H oxidase activity and reactive oxygen species (ROS) level. Overexpression of salusin-β exerted the opposite effects on vasomotor function and vascular remodeling, and PASMCs proliferation, migration, fibrosis and calcification. Conclusion: Increased salusin-β activity in PAs from PH rats contributes to PASMCs proliferation, migration, fibrosis, and calcification, leading to the imbalance of vascular contraction and relaxation and vascular remodeling through stimulating the production of NAD(P)H oxidase derived ROS.

Keywords: pulmonary artrial smooth muscle cells; pulmonary hypertension; reactive oxygen species; vascular remodeling; vasomotor function.