Cx43 Regulates Nicotine-Induced Proliferation and Migration of Distal Pulmonary Artery Smooth Muscle Cells by the ERK1/2 Signaling Pathway

Xiaomin Hou; Xinrong Xu; Lin Dong; Yanhua Li; Ruifeng Liang; Mingsheng Zhang; Jisheng Nie; Yiwei Shi; Xiaojiang Qin

doi:10.1002/jbt.70106

Cx43 Regulates Nicotine-Induced Proliferation and Migration of Distal Pulmonary Artery Smooth Muscle Cells by the ERK1/2 Signaling Pathway

J Biochem Mol Toxicol. 2025 Jan;39(1):e70106. doi: 10.1002/jbt.70106.

Authors

Xiaomin Hou^{1

2

3}, Xinrong Xu⁴, Lin Dong⁵, Yanhua Li⁶, Ruifeng Liang⁴, Mingsheng Zhang¹, Jisheng Nie^{4

7}, Yiwei Shi^{7

8

9}, Xiaojiang Qin^{2

4

7

8

9}

Affiliations

¹ Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi, China.
² Environmental Exposures Vascular Disease Institute, Shanxi Medical University, Taiyuan, Shanxi, China.
³ China Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, China.
⁴ School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, China.
⁵ Academy of Medical Science, Shanxi Medical University, Taiyuan, Shanxi, China.
⁶ Department of Foreign Languages, Shanxi Medical University, Taiyuan, Shanxi, China.
⁷ Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Taiyuan, Shanxi, China.
⁸ First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
⁹ Department of Pulmonary and Critical Care Medicine, NHC Key Laboratory of Pneumoconiosis, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.

PMID: 39718028
DOI: 10.1002/jbt.70106

Abstract

Pulmonary hypertension is a progressive disease associated with remodeling of the pulmonary vasculature. Excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) play important roles in nicotine-induced vascular injury. Connexin 43 (Cx43) is involved in intracellular communication and regulation of the pulmonary vasculature. However, the role of Cx43 and the potential mechanisms in PASMCs proliferation and migration induced by nicotine remains not very clear. In this study, we used both in vitro and in vivo models to explore the crucial role of Cx43 in pulmonary artery remodeling in nicotine treatment Tagln-Cre; Cx43^+/+ and Cx43 heterozygous (Tagln-Cre; Cx43^flox/+) or Cx43 Homozygous (Tagln-Cre; Cx43^flox/flox) deletion mice, and further explore the mechanism. We found that nicotine exposure led to modifications in the morphology and ultrastructure of pulmonary arteries in Tagln-Cre; Cx43^+/+ mice. Nicotine increased the Cx43 expression of pulmonary arteries and promoted the proliferation and migration of PASMCs of Tagln-Cre; Cx43^+/+ mice in a concentration-dependent manner by promoting ERK1/2 phosphorylation. Compared with the Tagln-Cre; Cx43^+/+ mice, the Tagln-Cre; Cx43^flox/+ mice were protected against increased ERK1/2 phosphorylation induced by nicotine. These results demonstrated that the downregulation of Cx43 reduced nicotine-induced proliferation and migration of distal PASMCs by inhibiting ERK1/2 phosphorylation.

Keywords: ERK1/2; connexin 43; nicotine; pulmonary artery remodeling; pulmonary artery smooth muscle cells.

MeSH terms

Animals
Cell Movement* / drug effects
Cell Proliferation* / drug effects
Connexin 43* / genetics
Connexin 43* / metabolism
MAP Kinase Signaling System* / drug effects
Male
Mice
Mice, Knockout
Mitogen-Activated Protein Kinase 1 / genetics
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / genetics
Mitogen-Activated Protein Kinase 3 / metabolism
Muscle, Smooth, Vascular / cytology
Muscle, Smooth, Vascular / drug effects
Muscle, Smooth, Vascular / metabolism
Myocytes, Smooth Muscle* / drug effects
Myocytes, Smooth Muscle* / metabolism
Nicotine* / pharmacology
Pulmonary Artery* / drug effects
Pulmonary Artery* / metabolism
Pulmonary Artery* / pathology

Substances

Connexin 43
Nicotine
GJA1 protein, mouse
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1

Grants and funding

This work was supported by the National Natural Science Foundation of China (No.82373622 and 82204042), the special fund for Science and Technology Innovation Teams of Shanxi Province (No.202304051001038), the Shanxi Province Science and Technology Cooperation and Exchange Special Project (No.202204041101022), Natural Science Research Project of Shanxi Province (202103021224227), Preferred funding projects for science and technology activities for overseas students in Shanxi Province (No.20220019), Shanxi Province Higher Education "Billion Project" Science and Technology Guidance Project (No. BYJL067), and the Open Subjects of the National Health Commission Key Laboratory of Pneumoconiosis (No.YKFKT006 and NHC202307).