TNF-α-Mediated Endothelial Cell Apoptosis Is Rescued by Hydrogen Sulfide

• Main Authors: Lorena Diaz Sanchez (Author), Lissette Sanchez-Aranguren (Author), Keqing Wang (Author), Corinne M. Spickett (Author), Helen R. Griffiths (Author), Irundika H. K. Dias (Author)
• Format: Book
• Published: MDPI AG, 2023-03-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antiox12030734; 2076-3921
• Keywords: vascular dysfunction; hydrogen sulfide; oxidative stress; inflammation; mitochondrial function; Therapeutics. Pharmacology; RM1-950
• Source: Antioxidants, Vol 12, Iss 3, p 734 (2023)

Endothelial dysfunction is implicated in the development and aggravation of cardiovascular complications. Among the endothelium-released vasoactive factors, hydrogen sulfide (H₂S) has been investigated for its beneficial effects on the vasculature through anti-inflammatory and redox-modulating regulatory mechanisms. Reduced H₂S bioavailability is reported in chronic diseases such as cardiovascular disease, diabetes, atherosclerosis and preeclampsia, suggesting the value of investigating mechanisms, by which H₂S acts as a vasoprotective gasotransmitter. We explored whether the protective effects of H₂S were linked to the mitochondrial health of endothelial cells and the mechanisms by which H₂S rescues apoptosis. Here, we demonstrate that endothelial dysfunction induced by TNF-α increased endothelial oxidative stress and induced apoptosis via mitochondrial cytochrome c release and caspase activation over 24 h. TNF-α also affected mitochondrial morphology and altered the mitochondrial network. Post-treatment with the slow-releasing H₂S donor, GYY4137, alleviated oxidising redox state, decreased pro-caspase 3 activity, and prevented endothelial apoptosis caused by TNF-α alone. In addition, exogenous GYY4137 enhanced S-sulfhydration of pro-caspase 3 and improved mitochondrial health in TNF-α exposed cells. These data provide new insights into molecular mechanisms for cytoprotective effects of H₂S via the mitochondrial-driven pathway.