Hydrogen sulfide in the pathogenesis of atherosclerosis and its therapeutic potential

Abstract

Hydrogen sulfide (H₂S) was the third gaseous transmitter to be discovered, along with nitric oxide and carbon monoxide, and has been proposed to be involved in numerous physiological processes and pathology of various diseases. Hyperhomocysteinemia is an independent risk factor for cardiovascular disease, including atherosclerosis. Atherosclerosis is characterized by multiple key events including endothelial dysfunction, monocyte infiltration and their differentiation into macrophages, conversion of lesion-resident macrophages into foam cells, and smooth muscle cell proliferation. Increasing evidence has indicated that H₂S plays a potentially significant role in all of these biological processes and that malfunction of H₂S homeostasis may contribute to the pathogenesis of atherosclerosis. Experiments have demonstrated that H₂S supplementation ameliorated many of these atherogenic processes and hence, such supplementation potentially may prove to be of therapeutic benefit in the prevention or treatment of atherosclerosis. H₂S levels may be induced by the administration of H₂S or H₂S donors, or alternatively be reduced by the administration of specific cystathionine β-synthase or cystathionine γ-lyase inhibitors. However, issues remain with the potential use of currently available H₂S-modulating agents in a clinical setting. This review will provide a description of the current literature on the involvement of H₂S in these key aspects of vascular biology that contribute to the development of atherosclerosis, as well as the therapeutic potential of currently available H₂S-modulating agents.

Keywords::

• atherosclerosis
• endoplasmic reticulum stress
• hydrogen sulfide
• hyperhomocysteinemia
• monocytes/macrophages
• NaHS
• oxidative stress
• smooth muscle cells

Acknowledgements

The authors gratefully acknowledge Ali Al-Hashimi for help with figure generation.

Financial & competing interests disclosure

This work was supported in part by research grants to Richard Austin from the Heart and Stroke Foundation of Ontario and the Canadian Institutes of Health Research. Financial support from St Joseph’s Healthcare Hamilton is acknowledged. Richard Austin is a Career Investigator of the Heart and Stroke Foundation of Ontario and holds the Amgen Canada Research Chair in the Division of Nephrology at St Joseph’s Healthcare and McMaster University.The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.