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FUNDC1-mediated mitophagy and HIF1α activation drives pulmonary hypertension during hypoxia

Hypoxic pulmonary hypertension (PH) is a progressive disease characterized by hyper-proliferation of pulmonary vascular cells including pulmonary artery smooth muscle cells (PASMCs) and can lead to right heart failure and early death. Selective degradation of mitochondria by mitophagy during hypoxia...

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Autores principales: Liu, Ruxia, Xu, Chunling, Zhang, Weilin, Cao, Yangpo, Ye, Jingjing, Li, Bo, Jia, Shi, Weng, Lin, Liu, Yingying, Liu, Lei, Zheng, Ming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304375/
https://www.ncbi.nlm.nih.gov/pubmed/35864106
http://dx.doi.org/10.1038/s41419-022-05091-2
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author Liu, Ruxia
Xu, Chunling
Zhang, Weilin
Cao, Yangpo
Ye, Jingjing
Li, Bo
Jia, Shi
Weng, Lin
Liu, Yingying
Liu, Lei
Zheng, Ming
author_facet Liu, Ruxia
Xu, Chunling
Zhang, Weilin
Cao, Yangpo
Ye, Jingjing
Li, Bo
Jia, Shi
Weng, Lin
Liu, Yingying
Liu, Lei
Zheng, Ming
author_sort Liu, Ruxia
collection PubMed
description Hypoxic pulmonary hypertension (PH) is a progressive disease characterized by hyper-proliferation of pulmonary vascular cells including pulmonary artery smooth muscle cells (PASMCs) and can lead to right heart failure and early death. Selective degradation of mitochondria by mitophagy during hypoxia regulates mitochondrial functions in many cells, however, it is not clear if mitophagy is involved in the pathogenesis of hypoxic PH. By employing the hypoxic mitophagy receptor Fundc1 knockout (KO) and transgenic (TG) mouse models, combined hypoxic PH models, the current study found that mitophagy is actively involved in hypoxic PH through regulating PASMC proliferation. In the pulmonary artery medium from hypoxic PH mice, mitophagy was upregulated, accompanied with the increased active form of FUNDC1 protein and the enhanced binding affinity of FUNDC1 with LC3B. In PASMCs, overexpression of FUNDC1 increased mitophagy and cell proliferation while knockdown of FUNDC1 inhibited hypoxia-induced mitophagy and PASMC proliferation. Stimulation of mitophagy by FUNDC1 in PASMCs elevated ROS production and inhibited ubiquitination of hypoxia inducible factor 1α (HIF1α), and inhibition of mitophagy by FUNDC1 knockdown or knockout abolished hypoxia-induced ROS-HIF1α upregulation. Moreover, Fundc1 TG mice developed severe hemodynamics changes and pulmonary vascular remodeling, and Fundc1 KO mice were much resistant to hypoxic PH. In addition, intraperitoneal injection of a specific FUNDC1 peptide inhibitor to block mitophagy ameliorated hypoxic PH. Our results reveal that during hypoxic PH, FUNDC1-mediated mitophagy is upregulated which activates ROS-HIF1α pathway and promotes PASMC proliferation, ultimately leads to pulmonary vascular remodeling and PH.
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spelling pubmed-93043752022-07-23 FUNDC1-mediated mitophagy and HIF1α activation drives pulmonary hypertension during hypoxia Liu, Ruxia Xu, Chunling Zhang, Weilin Cao, Yangpo Ye, Jingjing Li, Bo Jia, Shi Weng, Lin Liu, Yingying Liu, Lei Zheng, Ming Cell Death Dis Article Hypoxic pulmonary hypertension (PH) is a progressive disease characterized by hyper-proliferation of pulmonary vascular cells including pulmonary artery smooth muscle cells (PASMCs) and can lead to right heart failure and early death. Selective degradation of mitochondria by mitophagy during hypoxia regulates mitochondrial functions in many cells, however, it is not clear if mitophagy is involved in the pathogenesis of hypoxic PH. By employing the hypoxic mitophagy receptor Fundc1 knockout (KO) and transgenic (TG) mouse models, combined hypoxic PH models, the current study found that mitophagy is actively involved in hypoxic PH through regulating PASMC proliferation. In the pulmonary artery medium from hypoxic PH mice, mitophagy was upregulated, accompanied with the increased active form of FUNDC1 protein and the enhanced binding affinity of FUNDC1 with LC3B. In PASMCs, overexpression of FUNDC1 increased mitophagy and cell proliferation while knockdown of FUNDC1 inhibited hypoxia-induced mitophagy and PASMC proliferation. Stimulation of mitophagy by FUNDC1 in PASMCs elevated ROS production and inhibited ubiquitination of hypoxia inducible factor 1α (HIF1α), and inhibition of mitophagy by FUNDC1 knockdown or knockout abolished hypoxia-induced ROS-HIF1α upregulation. Moreover, Fundc1 TG mice developed severe hemodynamics changes and pulmonary vascular remodeling, and Fundc1 KO mice were much resistant to hypoxic PH. In addition, intraperitoneal injection of a specific FUNDC1 peptide inhibitor to block mitophagy ameliorated hypoxic PH. Our results reveal that during hypoxic PH, FUNDC1-mediated mitophagy is upregulated which activates ROS-HIF1α pathway and promotes PASMC proliferation, ultimately leads to pulmonary vascular remodeling and PH. Nature Publishing Group UK 2022-07-21 /pmc/articles/PMC9304375/ /pubmed/35864106 http://dx.doi.org/10.1038/s41419-022-05091-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Liu, Ruxia
Xu, Chunling
Zhang, Weilin
Cao, Yangpo
Ye, Jingjing
Li, Bo
Jia, Shi
Weng, Lin
Liu, Yingying
Liu, Lei
Zheng, Ming
FUNDC1-mediated mitophagy and HIF1α activation drives pulmonary hypertension during hypoxia
title FUNDC1-mediated mitophagy and HIF1α activation drives pulmonary hypertension during hypoxia
title_full FUNDC1-mediated mitophagy and HIF1α activation drives pulmonary hypertension during hypoxia
title_fullStr FUNDC1-mediated mitophagy and HIF1α activation drives pulmonary hypertension during hypoxia
title_full_unstemmed FUNDC1-mediated mitophagy and HIF1α activation drives pulmonary hypertension during hypoxia
title_short FUNDC1-mediated mitophagy and HIF1α activation drives pulmonary hypertension during hypoxia
title_sort fundc1-mediated mitophagy and hif1α activation drives pulmonary hypertension during hypoxia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304375/
https://www.ncbi.nlm.nih.gov/pubmed/35864106
http://dx.doi.org/10.1038/s41419-022-05091-2
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