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. Epub 2020 Nov 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Female
  • Humans
  • Injections, Intraperitoneal
  • MAP Kinase Signaling System
  • Male
  • Middle Aged
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / pathology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Plasminogen Activator Inhibitor 2 / administration & dosage
  • Plasminogen Activator Inhibitor 2 / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pulmonary Arterial Hypertension / metabolism*
  • Pulmonary Arterial Hypertension / pathology
  • Pulmonary Artery / metabolism*
  • Pulmonary Artery / pathology
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Plasminogen Activator Inhibitor 2
  • Proto-Oncogene Proteins c-akt