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Journal Article Ppublish 4 citations

PubMed: 38266576 DOI: 10.1016/j.redox.2024.103038

Endothelial HS-AMPK dysfunction upregulates the angiocrine factor PAI-1 and contributes to lung fibrosis.

Redox Biol 70:103038

Authors: Xiangqi Chen, Han Wang, Chuan Wu, Xiaoyan Li, Xiaojuan Huang, Yafeng Ren, Qiang Pu, Zhongwei Cao, Xiaoqiang Tang, Bi-Sen Ding

Affiliations

  • Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, NHC Key Laboratory of Chronobiology, Development and Related Diseases of Women and Children, Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
  • Department of Thoracic Surgery, National Frontier Center of Disease Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, NHC Key Laboratory of Chronobiology, Development and Related Diseases of Women and Children, Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
  • Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, NHC Key Laboratory of Chronobiology, Development and Related Diseases of Women and Children, Key Laboratory of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.

Abstract

Dysfunction of the vascular angiocrine system is critically involved in regenerative defects and fibrosis of injured organs. Previous studies have identified various angiocrine factors and found that risk factors such as aging and metabolic disorders can disturb the vascular angiocrine system in fibrotic organs. One existing key gap is what sense the fibrotic risk to modulate the vascular angiocrine system in organ fibrosis. Here, using human and mouse data, we discovered that the metabolic pathway hydrogen sulfide (HS)-AMP-activated protein kinase (AMPK) is a sensor of fibrotic stress and serves as a key mechanism upregulating the angiocrine factor plasminogen activator inhibitor-1 (PAI-1) in endothelial cells to participate in lung fibrosis. Activation of the metabolic sensor AMPK was inhibited in endothelial cells of fibrotic lungs, and AMPK inactivation was correlated with enriched fibrotic signature and reduced lung functions in humans. The inactivation of endothelial AMPK accelerated lung fibrosis in mice, while the activation of endothelial AMPK with metformin alleviated lung fibrosis. In fibrotic lungs, endothelial AMPK inactivation led to YAP activation and overexpression of the angiocrine factor PAI-1, which was positively correlated with the fibrotic signature in human fibrotic lungs and inhibition of PAI-1 with Tiplaxtinin mitigated lung fibrosis. Further study identified that the deficiency of the antioxidative gas metabolite HS accounted for the inactivation of AMPK and activation of YAP-PAI-1 signaling in endothelial cells of fibrotic lungs. HS deficiency was involved in human lung fibrosis and HS supplement reversed mouse lung fibrosis in an endothelial AMPK-dependent manner. These findings provide new insight into the mechanism underlying the deregulation of the vascular angiocrine system in fibrotic organs.

MeSH

Plasminogen Activator Inhibitor 1, Cells, Lung, Fibrosis, Endothelial Cells

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