Hypoxia induces pulmonary artery smooth muscle dysfunction through mitochondrial fragmentation-mediated endoplasmic reticulum stress.

Bing Zhuan,Qun Yuan,Zhao Yang,Ming-Deng Wang,Xi Wang,Jun Xie,Zhi-Cai Li

doi:10.18632/aging.103892

Abstract

Pulmonary arterial hypertension (PAH) is characterized by pulmonary artery smooth muscle cell (PASMC) dysfunction. However, the underlying mechanisms of PASMC dysfunction remain largely unknown. Here, we show that mitochondrial fragmentation contributes to PASMC dysfunction through enhancement of endoplasmic reticulum (ER) stress. PASMC dysfunction accompanied by mitochondrial fragmentation and ER stress was observed in the pulmonary arteries of hypoxia-induced rats with PAH, as well as isolated PASMCs under hypoxia. Treatment with Mdivi-1 inhibited mitochondrial fragmentation and ER stress and improved PASMC function in isolated PASMCs under hypoxia, while Drp1 overexpression increased mitochondrial fragmentation and ER stress, impairing PASMC function in isolated PASMCs under normoxia. However, inhibition of ER stress using ER stress inhibitors showed a negligible effect on mitochondrial morphology but improved PASMC function during hypoxia. Additionally, we found that mitochondrial fragmentation-promoted ER stress was dependent on mitochondrial reactive oxygen species. Furthermore, inhibition of mitochondrial fragmentation using Mdivi-1 attenuated mitochondrial fragmentation and ER stress in hypoxic PASMCs and improved the pulmonary artery smooth muscle function in hypoxic rats. These results suggest that hypoxia induces pulmonary artery smooth muscle dysfunction through mitochondrial fragmentation-mediated ER stress and that mitochondrial morphology is a potential target for treatment of hypoxia-induced pulmonary artery smooth muscle dysfunction.

Highlights

Pulmonary arteries irrigate pulmonary alveoli, where gas exchange takes place between the bloodstream and the lungs
PE seemed to be potent in the stimulation of pulmonary vasoconstriction in normoxic and hypoxic rats when PE-induced vasoconstriction was presented as percentage of maximal contraction (Figure 1C), PE-induced vasoconstriction was reduced in pulmonary artery rings in hypoxic rats when it was presented as contraction force per tissue weight (g/mg tissue) (Figure 1D), suggesting the occurrence of pulmonary artery smooth muscle cell (PASMC) dysfunction
These results suggested that mitochondrial morphology is a potential target for the treatment of hypoxia-induced pulmonary artery smooth muscle dysfunction

Summary

Introduction

Pulmonary arteries irrigate pulmonary alveoli, where gas exchange takes place between the bloodstream and the lungs. Chronic hypoxia increases pulmonary artery smooth muscle cell (PASMC) proliferation and dysfunction, leading to a narrowing of pulmonary circulation, poor blood and tissue oxygenation, and an increased workload in the right portion of the heart www.aging-us.com [3, 4]. This mechanism is relevant for conditions such as pulmonary arterial hypertension (PAH), a chronic and incurable disease. PAH is characterized by increased pulmonary arterial blood pressure and right ventricular hypertrophy [5,6,7]. Understanding the underlying mechanisms involved in PAH should help design specific and efficient therapies for this life-threatening disease

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Results

Conclusion