Inhibition of Shp2 ameliorates monocrotaline-induced pulmonary arterial hypertension in rats.

Abstract

BACKGROUND:

Src homology 2 containing protein tyrosine phosphatase (PTP) 2 (Shp2) is a typical tyrosine phosphatase interacting with receptor tyrosine kinase to regulate multiple signaling pathways in diverse pathological processes. Here, we will investigate the effect of Shp2 inhibition on pulmonary arterial hypertension (PAH) in a rat model and its potential cellular and molecular mechanisms underlying.

METHODS:

Monocrotaline (MCT)-induced PAH rat model was used in this study. Phps-1, a highly selective inhibitor for Shp2, was administered from 21 days to 35 days after MCT single-injection. Microcatheter method was applied to detected hemodynamic parameters. Histological methods were used to determine PVR changes in PAH rats. Moreover, cultured pulmonary artery smooth muscle cells (PASMCs) treated by platelet-derived growth factor (PDGF) with or without Phps-1 was used to investigate the potential cellular and molecular mechanisms underlying in vitro.

RESULTS:

Inhibition of Shp2 significantly attenuated MCT-induced increases of mean pulmonary arterial pressure (mPAP), right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in rats. Shp2 inhibition effectively decreased thickening of pulmonary artery media and cardiomyocyte hypertrophy as well as perivascular and myocardial fibrosis in MCT-treated rats. Moreover, Shp2 inhibition ameliorated muscularization of pulmonary arterioles in MCT-induced PAH rats. Shp2 inhibition significantly reduced platelet-derived growth factor (PDGF)-triggered proliferation and migration of human pulmonary artery smooth muscle cells (PASMCs), which might be attributed to the inactivations of Akt and Stat3 pathways.

CONCLUSIONS:

Shp2 contributes to the development of PAH in rats, which might be a potential target for the treatment of PAH.

• Authors: Yusheng Cheng, Min Yu, Jian Xu, Mengyu He, Hong Wang, Hui Kong, Weiping Xie
• Journal: BMC pulmonary medicine (BMC Pulm Med) Vol. 18 Issue 1 Pg. 130 (Aug 07 2018) ISSN: 1471-2466 [Electronic] England
• PMID: 30086741 (Publication Type: Journal Article)

Chemical References

• Platelet-Derived Growth Factor
• Monocrotaline
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Ptpn11 protein, rat

Topics

• Animals
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Hypertension, Pulmonary (chemically induced, metabolism, physiopathology)
• Hypertrophy, Right Ventricular (metabolism)
• Lung (drug effects, pathology)
• Male
• Monocrotaline
• Myocytes, Smooth Muscle (drug effects)
• Platelet-Derived Growth Factor (metabolism)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (antagonists & inhibitors)
• Pulmonary Artery (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)