Maresin-1 protects against pulmonary arterial hypertension by improving mitochondrial homeostasis through ALXR/HSP90α axis

Min Liu; Huixiang He; Fenling Fan; Lejia Qiu; Feng Zheng; Youfei Guan; Guangrui Yang; Lihong Chen

doi:10.1016/j.yjmcc.2023.05.005

Maresin-1 protects against pulmonary arterial hypertension by improving mitochondrial homeostasis through ALXR/HSP90α axis

J Mol Cell Cardiol. 2023 Aug:181:15-30. doi: 10.1016/j.yjmcc.2023.05.005. Epub 2023 May 25.

Authors

Min Liu¹, Huixiang He¹, Fenling Fan², Lejia Qiu³, Feng Zheng¹, Youfei Guan¹, Guangrui Yang⁴, Lihong Chen⁵

Affiliations

¹ Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China.
² Division of Pulmonary Vascular Disease, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
³ Health Science Center, East China Normal University, Shanghai 200241, China.
⁴ School of Bioengineering, Dalian University of Technology, Dalian 116024, China.
⁵ Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China; Health Science Center, East China Normal University, Shanghai 200241, China. Electronic address: lihong@dmu.edu.cn.

PMID: 37244057
DOI: 10.1016/j.yjmcc.2023.05.005

Abstract

Aims: Pulmonary arterial hypertension (PAH) is a progressive and lethal disease characterized by continuous proliferation of pulmonary arterial smooth muscle cell (PASMCs) and increased pulmonary vascular remodeling. Maresin-1 (MaR1) is a member of pro-resolving lipid mediators and exhibits protective effects on various inflammation-related diseases. Here we aimed to study the role of MaR1 in the development and progression of PAH and to explore the underlying mechanisms.

Methods and results: We evaluated the effect of MaR1 treatment on PAH in both monocrotaline (MCT)-induced rat and hypoxia+SU5416 (HySu)-induced mouse models of pulmonary hypertension (PH). Plasma samples were collected from patients with PAH and rodent PH models to examine MaR1 production. Specific shRNA adenovirus or inhibitors were used to block the function of MaR1 receptors. The data showed that MaR1 significantly prevented the development and blunted the progression of PH in rodents. Blockade of the function of MaR1 receptor ALXR, but not LGR6 or RORα, with BOC-2, abolished the protective effect of MaR1 against PAH development and reduced its therapeutic potential. Mechanistically, we demonstrated that the MaR1/ALXR axis suppressed hypoxia-induced PASMCs proliferation and alleviated pulmonary vascular remodeling by inhibiting mitochondrial accumulation of heat shock protein 90α (HSP90α) and restoring mitophagy.

Conclusion: MaR1 protects against PAH by improving mitochondrial homeostasis through ALXR/HSP90α axis and represents a promising target for PAH prevention and treatment.

Keywords: ALXR; HSP90α; Maresin-1; Mitochondrial homeostasis; Pulmonary arterial hypertension.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Proliferation
Cells, Cultured
Disease Models, Animal
Familial Primary Pulmonary Hypertension
Heat-Shock Proteins / adverse effects
Heat-Shock Proteins / metabolism
Hypertension, Pulmonary* / metabolism
Hypoxia / metabolism
Mice
Monocrotaline
Myocytes, Smooth Muscle / metabolism
Pulmonary Arterial Hypertension* / metabolism
Pulmonary Artery
Rats
Vascular Remodeling

Substances

Heat-Shock Proteins
Monocrotaline