Endothelial Cell-Derived SO2 Controls Endothelial Cell Inflammation, Smooth Muscle Cell Proliferation, and Collagen Synthesis to Inhibit Hypoxic Pulmonary Vascular Remodelling.

Xin Liu,Xiuli Wang,Yaqian Huang,Guosheng Yang,Yongyan Hu,Guozhen Chen,Yuanyuan Wang,Chufan Sun,Yinghong Tao,Jingyuan Song,Hongfang Jin,Shangyue Zhang,Junbao Du,Dingfang Bu,Andrea Berenyiova

doi:10.1155/2021/5577634

Abstract

Hypoxic pulmonary vascular remodelling (PVR) is the major pathological basis of aging-related chronic obstructive pulmonary disease and obstructive sleep apnea syndrome. The pulmonary artery endothelial cell (PAEC) inflammation, and pulmonary artery smooth muscle cell (PASMC) proliferation, hypertrophy and collagen remodelling are the important pathophysiological components of PVR. Endogenous sulfur dioxide (SO2) was found to be a novel gasotransmitter in the cardiovascular system with its unique biological properties. The study was aimed to investigate the role of endothelial cell- (EC-) derived SO2 in the progression of PAEC inflammation, PASMC proliferation, hypertrophy and collagen remodelling in PVR and the possible mechanisms. EC-specific aspartic aminotransferase 1 transgenic (EC-AAT1-Tg) mice were constructed in vivo. Pulmonary hypertension was induced by hypoxia. Right heart catheterization and echocardiography were used to detect mouse hemodynamic changes. Pathologic analysis was performed in the pulmonary arteries. High-performance liquid chromatography was employed to detect the SO2 content. Human PAECs (HPAECs) with lentiviruses containing AAT1 cDNA or shRNA and cocultured human PASMCs (HPASMCs) were applied in vitro. SO2 probe and enzyme-linked immunosorbent assay were used to detect the SO2 content and determine p50 activity, respectively. Hypoxia caused a significant reduction in SO2 content in the mouse lung and HPAECs and increases in right ventricular systolic pressure, pulmonary artery wall thickness, muscularization, and the expression of PAEC ICAM-1 and MCP-1 and of PASMC Ki-67, collagen I, and α-SMA (p < 0.05). However, EC-AAT1-Tg with sufficient SO2 content prevented the above increases induced by hypoxia (p < 0.05). Mechanistically, EC-derived SO2 deficiency promoted HPAEC ICAM-1 and MCP-1 and the cocultured HPASMC Ki-67 and collagen I expression, which was abolished by andrographolide, an inhibitor of p50 (p < 0.05). Meanwhile, EC-derived SO2 deficiency increased the expression of cocultured HPASMC α-SMA (p < 0.05). Taken together, these findings revealed that EC-derived SO2 inhibited p50 activation to control PAEC inflammation in an autocrine manner and PASMC proliferation, hypertrophy, and collagen synthesis in a paracrine manner, thereby inhibiting hypoxic PVR.

Highlights

Aging is an important risk factor for a variety of diseases [1,2,3]
In the present study, we further explored whether endothelial cell- (EC-)derived SO2 might control pulmonary artery endothelial cell (PAEC) inflammation in an autocrine manner and control pulmonary artery smooth muscle cell (PASMC) proliferation, hypertrophy, and collagen deposition in a paracrine manner to reveal a new mechanism for PAEC inflammation and PAEC-PASMC communication in the control of PASMC proliferation, hypertrophy, and collagen remodelling by SO2
By Western blot analysis and SO2 fluorescent probe method, we further confirmed that compared with the control vehicle group, the levels of AAT1 protein and SO2 were downregulated in hypoxic Human PAECs (HPAECs), whereas overexpression of AAT1 significantly improved the endogenous SO2 level in endothelial cells (ECs) and prevented the decrease in EC-derived SO2 caused by hypoxia (Figures 1(c) and 1(d)) (p < 0:05)

Summary

Introduction

Aging is an important risk factor for a variety of diseases [1,2,3]. With the increase of the global elderly population, the incidence of aging and age-related diseases such as chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea syndrome (OSAS) has been gradually increased [4, 5]. Hypoxic pulmonary hypertension (PH) and pulmonary vascular remodelling (PVR) are the critical pathological basis. PVR includes pulmonary artery endothelial cell (PAEC) dysfunction, and pulmonary artery smooth muscle cell (PASMC) proliferation, hypertrophy, and collagen accumulation [6,7,8,9]. Previous studies reported that an imbalance among small vasoactive molecules played a critical role in the progression of PVR. The imbalance among protein-derived bioactive molecules, active lipid mediators, small nucleic acids, and gaseous signalling molecules is predominantly involved in the pulmonary artery structural changes and the abnormal vasoconstriction and vasorelaxation [10,11,12,13,14,15,16]. The mechanisms underlying the excessive PAEC inflammation, PASMC proliferation, hypertrophy, and collagen remodelling remain unclear

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