The Effect of Hydrogen Sulphide on TNF-α-induced Endothelial Dysfunction

Abstract

Cardiovascular disease is the leading cause of morbidity and mortality globally. Endothelial dysfunction (ED) is implicated in the development and aggravation of cardiovascular complications. There is growing interest in understanding the pathophysiological mechanisms underlying ED and identifying therapeutic strategies that may prevent or reduce the risk of vascular complications and associated diseases. Hydrogen sulphide (H₂S) is an endogenous gasotransmitter that can act as an essential biological mediator. In the vasculature, H₂S can mediate beneficial effects through anti-inflammatory and redox-modulating regulatory mechanisms. Reduced H₂S bioavailability is reported in chronic diseases such as atherosclerosis, diabetes, hypertension and preeclampsia, suggesting the possible value of investigating H₂S as a therapeutic strategy for vascular-related conditions.
The study aimed to examine the cytoprotective roles of H₂S against TNF-α-mediated ED. Human umbilical vein endothelial cells (HUVECs) were stimulated with TNF-α (1 ng/ml) followed by a slow H₂S-releasing donor, GYY4137, post-treatment (100 μM). TNF-α proved to be an efficient agent enabling ED as evidence enhanced oxidising redox state, inflammation and apoptosis via mitochondrial-dependent downstream signalling pathway. Confocal microscopy and gene-transcriptional expression analysis revealed that TNF-α affects mitochondrial dynamics, characterised as well by fragmentation of the organelle. GYY4137 post-treatment balances the redox state that alleviates endothelial inflammation, mitochondrial dysfunction, and pro-apoptotic signalling. In addition, GYY4137 enhanced protein S-sulfhydration of Keap1 and caspase 3, stimulating Nrf2-downstream response and inhibiting caspase 3/7 activity, respectively.
In conclusion, the findings of this research contribute to expanding the understanding of the overall role H₂S underlying mechanisms and indicate that the slow-releasing H₂S donor may have putative therapeutic applications in inflammation-associated ED.

Date of Award	Sept 2022
Original language	English
Awarding Institution	Aston University
Supervisor	Irundika Dias (Supervisor)