TMEM16A Regulates Pulmonary Arterial Smooth Muscle Cells Proliferation via p38MAPK/ERK Pathway in High Pulmonary Blood Flow-Induced Pulmonary Arterial Hypertension

Dongli Liu; Kai Wang; Danyan Su; Yanyun Huang; Lifeng Shang; Yijue Zhao; Jinglin Huang; Yusheng Pang

doi:10.1159/000511267

TMEM16A Regulates Pulmonary Arterial Smooth Muscle Cells Proliferation via p38MAPK/ERK Pathway in High Pulmonary Blood Flow-Induced Pulmonary Arterial Hypertension

J Vasc Res. 2020 Dec 11;58(1):27-37. doi: 10.1159/000511267. Online ahead of print.

Authors

Dongli Liu¹, Kai Wang^{1

2}, Danyan Su¹, Yanyun Huang¹, Lifeng Shang¹, Yijue Zhao¹, Jinglin Huang¹, Yusheng Pang³

Affiliations

¹ Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
² Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
³ Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China, pangyush@163.com.

PMID: 33311015
DOI: 10.1159/000511267

Abstract

Objective: Pulmonary arterial hypertension (PAH) is a complex disease of the small pulmonary arteries that is mainly characterized by vascular remodeling. It has been demonstrated that excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) plays a pivotal role in vascular remodeling during PAH. The present study was undertaken to explore the role of TMEM16A in regulating PASMCs proliferation in high pulmonary blood flow-induced PAH.

Methods: Aortocaval shunt surgery was undertaken to establish an animal model. Pulmonary artery pressure and pulmonary vascular structure remodeling (PVSR) were tested. Immunohistochemical staining and Western blot were performed to investigate the expression of TMEM16A. The proliferation of PASMCs was tested by the MTT assay. After treating PASMCs with TMEM16A-siRNA, the expression of proliferating cell nuclear antigen (PCNA), phosphorylated p38 mitogen-activated protein kinase (p-p38MAPK), and phosphorylated extracellular signal-regulated kinase (p-ERK) signaling in PASMCs were tested.

Results: PAH and PVSR developed 11 weeks postoperation. Elevated expression of TMEM16A accompanied by high expression of PCNA in pulmonary arteries of the shunt group was observed. The increased proliferation of PASMCs and increased expression of TMEM16A and PCNA, along with activated p-p38MAPK and p-ERK signaling in PASMCs of the shunt group, were all attenuated by siRNA-specific TMEM16A knockdown.

Conclusion: TMEM16A regulates PASMCs proliferation in high pulmonary blood flow-induced PAH, and the p38MAPK/ERK signaling pathway is probably involved.

Keywords: High blood flow; Mitogen-activated protein kinase signaling pathway; Pulmonary arterial hypertension; Pulmonary arterial smooth muscle cells proliferation; TMEM16A.