NDUFA4L2 in smooth muscle promotes vascular remodeling in hypoxic pulmonary arterial hypertension

Autor: Tianyan Wang, Xiaowei Nie, Yanli Li, Yun Liu, Zengxian Sun, Qian Wang, Jinquan Zhu
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Mitochondrion
Pharmacology
p38 Mitogen-Activated Protein Kinases
Muscle
Smooth
Vascular
0302 clinical medicine
pulmonary arterial hypertension
Malondialdehyde
Hypoxia
Gene knockdown
Cell Hypoxia
medicine.anatomical_structure
030220 oncology & carcinogenesis
Molecular Medicine
Original Article
medicine.symptom
Oxidation-Reduction
proliferation
Myocytes
Smooth Muscle
Pulmonary Artery
Vascular Remodeling
pulmonary vascular remodelling
Models
Biological
Vascular remodelling in the embryo
03 medical and health sciences
Oxygen Consumption
medicine.artery
medicine
Animals
Humans
Gene Silencing
RNA
Messenger
Rats
Wistar
Cell Proliferation
Aldehydes
Arachidonate 5-Lipoxygenase
Electron Transport Complex I
business.industry
Endothelial Cells
Original Articles
Cell Biology
Hypoxia (medical)
medicine.disease
Pulmonary hypertension
NDUFA4L2
Disease Models
Animal
030104 developmental biology
Gene Expression Regulation
Apoptosis
Pulmonary artery
Vascular resistance
Reactive Oxygen Species
business
Zdroj: Journal of Cellular and Molecular Medicine
ISSN: 1582-4934
1582-1838
DOI: 10.1111/jcmm.16193
Popis: Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance and obliterative pulmonary vascular remodelling (PVR). The imbalance between the proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMCs) is an important cause of PVR leading to PAH. Mitochondria play a key role in the production of hypoxia‐induced pulmonary hypertension (HPH). However, there are still many issues worth studying in depth. In this study, we demonstrated that NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 like 2 (NDUFA4L2) was a proliferation factor and increased in vivo and in vitro through various molecular biology experiments. HIF‐1α was an upstream target of NDUFA4L2. The plasma levels of 4‐hydroxynonene (4‐HNE) were increased both in PAH patients and hypoxic PAH model rats. Knockdown of NDUFA4L2 decreased the levels of malondialdehyde (MDA) and 4‐HNE in human PASMCs in hypoxia. Elevated MDA and 4‐HNE levels might be associated with excessive ROS generation and increased expression of 5‐lipoxygenase (5‐LO) in hypoxia, but this effect was blocked by siNDUFA4L2. Further research found that p38‐5‐LO was a downstream signalling pathway of PASMCs proliferation induced by NDUFA4L2. Up‐regulated NDUFA4L2 plays a critical role in the development of HPH, which mediates ROS production and proliferation of PASMCs, suggesting NDUFA4L2 as a potential new therapeutic target for PAH.
Databáze: OpenAIRE
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