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  3. Plasminogen activator Inhibitor-2 inhibits pulmonary arterial smooth muscle cell proliferation in pulmonary arterial hypertension via PI3K/Akt and ERK signaling

Plasminogen activator Inhibitor-2 inhibits pulmonary arterial smooth muscle cell proliferation in pulmonary arterial hypertension via PI3K/Akt and ERK signaling

  • Exp Cell Res. 2021 Jan 1;398(1):112392. doi: 10.1016/j.yexcr.2020.112392.
Shuai Zhang 1,  Jing Wang 2,  Xianmei Qi 3,  Xincao Tao 1,  Wanmu Xie 1,  Jun Wan 1,  Ying H Shen 4,  Zhenguo Zhai 5
Affiliations

Affiliations

  • 1 Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China; National Clinical Research Center for Respiratory Diseases, Beijing, China.
  • 2 Department of Pulmonary and Critical Care Medicine, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
  • 3 State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Pathophysiology, Peking Union Medical College, Beijing, China; Department of Respiratory Medicine, Capital Medical University, Beijing, China.
  • 4 Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA; Department of Cardiovascular Surgery, Texas Heart Institute, Houston, TX, USA.
  • 5 Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China; National Clinical Research Center for Respiratory Diseases, Beijing, China. Electronic address: [email protected].
PMID: 33227315 DOI: 10.1016/j.yexcr.2020.112392
Abstract

Background: The proliferation of pulmonary arterial smooth muscle cells (PASMCs) and subsequent pulmonary vascular remodeling leads to pulmonary arterial hypertension (PAH). Understanding the underlying mechanisms and identifying molecules that can suppress PASMCs proliferation is critical for developing effective pharmacological treatment. We previously showed that plasminogen activator inhibitor-2 (PAI-2) inhibited human PASMC (hPASMCs) proliferation in vitro. However, its inhibitory effect on PAH remains to be determined, and the mechanism remains to be illustrated.

Methods: We compared serum PAI-2 levels between PAH patients and healthy controls, and examined the correlation between PAI-2 level and disease severity. In monocrotaline-induced PAH rats, we examined the effects of exogenous PAI-2 administration on pulmonary vascular remodeling and PAH development. The effect of PAI-2 and potential mechanisms was further examined in cultured hPASMCs.

Results: The serum PAI-2 was decreased in PAH patients compared with controls. PAI-2 level was negatively correlated with mean pulmonary arterial pressure and estimated systolic pulmonary arterial pressure in ultrasonic cardiogram, while positively correlated with 6-min walking distance. In rats, administration of exogenous PAI-2 significantly reversed monocrotaline-induced PAH, as indicated by the decrease in right ventricle systolic pressure, right ventricular hypertrophy index and percent media thickness of pulmonary arterioles. Further mechanistic investigation in hPASMCs showed that PAI-2 inhibited cell proliferation by preventing the activation of PI3K/Akt and ERK pathways.

Conclusion: PAI-2 is downregulated in PAH patients. PAI-2 attenuates PAH development by suppressing hPASMCs proliferation via the inhibition of PI3K/Akt and ERK pathways. PAI-2 may serve as a potential biomarker and therapeutic target for PAH.

Keywords

ERK; PI3K/Akt; Plasminogen activator inhibitor-2; Proliferation; Pulmonary arterial hypertension.

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