Endothelial H2S-AMPK dysfunction upregulates the angiocrine factor PAI-1 and contributes to lung fibrosis

Dysfunction of the vascular angiocrine system plays a critical role in regenerative failures and fibrosis in injured organs. Previous research has identified various angiocrine factors and noted that risk factors like aging and metabolic disorders can disrupt this system in fibrotic tissues. However, a significant gap remains in understanding how fibrotic risk is sensed and how it modulates the vascular angiocrine system in organ fibrosis.

In this study, using data from humans and mice, we identified the hydrogen sulfide (H2S)-AMP-activated protein kinase (AMPK) metabolic pathway as a key sensor of fibrotic stress. This pathway regulates the angiocrine factor plasminogen activator inhibitor-1 (PAI-1) in endothelial cells, contributing to lung fibrosis. We found that AMPK activation was inhibited in the endothelial cells of fibrotic lungs, with its inactivation correlating with a heightened fibrotic signature and diminished lung function in humans. In mice, loss of endothelial AMPK accelerated lung fibrosis, while activating AMPK with metformin alleviated the condition.

In fibrotic lungs, the inactivation of endothelial AMPK led to the activation of YAP and increased expression of PAI-1, which correlated positively with the fibrotic signature observed in human samples. Inhibition of PAI-1 with Tiplaxtinin helped reduce lung fibrosis. Further investigation revealed that a deficiency in the antioxidative gas H2S contributed to AMPK inactivation and YAP-PAI-1 signaling activation in endothelial cells within fibrotic lungs. H2S deficiency was linked to human lung fibrosis, and supplementation with H2S reversed lung fibrosis in mice in an AMPK-dependent manner. These findings offer new insights into the mechanisms behind the PAI-039 deregulation of the vascular angiocrine system in fibrotic organs.