Resistin-like molecule \u03b2 acts as a mitogenic factor in hypoxic pulmonary hypertension via the Ca2+-dependent PI3K/Akt/mTOR and PKC/MAPK signaling pathways

Heshen Tian,Ruicheng Hu,Ying Wu,Yongliang Jiang,Linwei Li,Lei Liu,Ruiwen Wang,Lianzhi Ji,Guoyu Liu,Aiguo Dai,Liming Zhu,Chulan Yang,Yanyan Fang

doi:10.1186/s12931-020-01598-4

Abstract

BackgroundPulmonary arterial smooth muscle cell (PASMC) proliferation plays a crucial role in hypoxia-induced pulmonary hypertension (HPH). Previous studies have found that resistin-like molecule β (RELM-β) is upregulated de novo in response to hypoxia in cultured human PASMCs (hPASMCs). RELM-β has been reported to promote hPASMC proliferation and is involved in pulmonary vascular remodeling in patients with PAH. However, the expression pattern, effects, and mechanisms of action of RELM-β in HPH remain unclear.MethodsWe assessed the expression pattern, mitogenetic effect, and mechanism of action of RELM-β in a rat HPH model and in hPASMCs.ResultsOverexpression of RELM-β caused hemodynamic changes in a rat model of HPH similar to those induced by chronic hypoxia, including increased mean right ventricular systolic pressure (mRVSP), right ventricular hypertrophy index (RVHI) and thickening of small pulmonary arterioles. Knockdown of RELM-β partially blocked the increases in mRVSP, RVHI, and vascular remodeling induced by hypoxia. The phosphorylation levels of the PI3K, Akt, mTOR, PKC, and MAPK proteins were significantly up- or downregulated by RELM-β gene overexpression or silencing, respectively. Recombinant RELM-β protein increased the intracellular Ca2+ concentration in primary cultured hPASMCs and promoted hPASMC proliferation. The mitogenic effects of RELM-β on hPASMCs and the phosphorylation of PI3K, Akt, mTOR, PKC, and MAPK were suppressed by a Ca2+ inhibitor.ConclusionsOur findings suggest that RELM-β acts as a cytokine-like growth factor in the development of HPH and that the effects of RELM-β are likely to be mediated by the Ca2+-dependent PI3K/Akt/mTOR and PKC/MAPK pathways.

Highlights

Hypoxia-induced pulmonary hypertension (HPH) is a progressive and devastating complication of chronic obstructive pulmonary disease (COPD) that contributes to the morbidity and mortality of patients with various types of lung/heart diseases [1, 2]
Abnormal pulmonary arterial smooth muscle cell (PASMC) proliferation is involved in hypoxia induces pulmonary vascular remodeling (HPVR) due to narrowing of the lumen and an increase in the pulmonary circulatory resistance resulting in pulmonary arterial hypertension (PAH) [1, 5, 6]
We investigated the role of resistin-like molecule β (RELM-β) in Pulmonary arterial smooth muscle cells (PASMCs) proliferation and determined whether the mitogenic effect of resistin-like molecule (RELM)-β is mediated by the PI3K/Akt/mTOR and protein kinase C (PKC)/ MAPK signaling pathways and whether Ca2+ is involved in this process

Summary

Introduction

Hypoxia-induced pulmonary hypertension (HPH) is a progressive and devastating complication of chronic obstructive pulmonary disease (COPD) that contributes to the morbidity and mortality of patients with various types of lung/heart diseases [1, 2]. Abnormal pulmonary arterial smooth muscle cell (PASMC) proliferation is involved in HPVR due to narrowing of the lumen and an increase in the pulmonary circulatory resistance resulting in pulmonary arterial hypertension (PAH) [1, 5, 6]. Further studies have proved that high levels of RLEM-β are present in patients with PAH, and RLEM-β overexpression significantly enhances proliferation of transfected hPASMCs [12, 13]. This evidence suggests that RELM-β may play an important role in the HPH development due to its mitogenic effect. Pulmonary arterial smooth muscle cell (PASMC) proliferation plays a crucial role in hypoxia-induced pulmonary hypertension (HPH). The expression pattern, effects, and mechanisms of action of RELM-β in HPH remain unclear

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