Disruption of sphingolipid metabolism triggers lung vascular inflammation and aging-like changes under hypoxia through VDAC1-mediated mitochondrial DNA release.

The lung, a key organ for oxygen exchange, is particularly susceptible to high-altitude hypoxic stress. Hypoxia induces vascular impairment, which is characterized by vascular inflammatory responses and aging-like changes. Lipid metabolism has been shown to be closely associated with cellular homeostasis and membrane balance. However, the alterations in pulmonary lipid metabolism in response to high-altitude hypoxia are not fully characterized. In this study, model mice were subjected to a hypobaric chamber at an altitude of 5500 m for 3 days, and pulmonary microvascular endothelial cells (PMVECs) were cultured under 1% oxygen for 18 h to simulate the effects of acute severe hypoxia. High-altitude hypoxia significantly disrupted lung sphingolipid metabolism, accompanied by inflammation and aging-like changes in mice. Moreover, C24-Ceramide (Cer) and its synthase (CERS2) were significantly increased in PMVECs. C24-Cer was identified to bind to voltage-dependent anion channel 1 (VDAC1) (a mitochondrial outer membrane protein), which promoted mitochondrial DNA (mtDNA) release and subsequently induced the inflammation and aging-like changes by activating the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway. Inhibition of C24-Cer or VDAC1 oligomerization by si-Cers2 or VBIT-4 could significantly reduce mtDNA release and alleviate inflammation and aging-like changes in the PMVECs and lung tissue under hypoxia. Our present work provides a novel and potential therapeutic target for high-altitude hypoxia-related vascular diseases.