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      Sulfide regulation of cardiovascular function in health and disease

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          Abstract

          Hydrogen sulfide (H 2S) has emerged as a gaseous signalling molecule with crucial implications for cardiovascular health. H 2S is involved in many biological functions, including interactions with nitric oxide, activation of molecular signalling cascades, post-translational modifications and redox regulation. Various preclinical and clinical studies have shown that H 2S and its synthesizing enzymes — cystathionine γ-lyase, cystathionine β-synthase and 3-mercaptosulfotransferase — can protect against cardiovascular pathologies, including arrhythmias, atherosclerosis, heart failure, myocardial infarction and ischaemia–reperfusion injury. The bioavailability of H 2S and its metabolites, such as hydropersulfides and polysulfides, is substantially reduced in cardiovascular disease and has been associated with single-nucleotide polymorphisms in H 2S synthesis enzymes. In this Review, we highlight the role of H 2S, its synthesizing enzymes and metabolites, their roles in the cardiovascular system, and their involvement in cardiovascular disease and associated pathologies. We also discuss the latest clinical findings from the field and outline areas for future study.

          Abstract

          Hydrogen sulfide (H 2S) is a gaseous signalling molecule with important roles in cardiovascular health and disease. In this Review, Kevil and colleagues discuss the role of H 2S, its synthesizing enzymes and metabolites, their roles in the cardiovascular system, and their involvement in cardiovascular disease and associated pathologies.

          Key points

          • Hydrogen sulfide (H 2S) has a crucial role in regulating cardiovascular function; reduced bioavailability is associated with cardiovascular pathologies, including arrhythmias, heart failure, ischaemic myocardial dysfunction and peripheral vascular disease.

          • H 2S and its synthesizing enzymes, including cystathionine γ-lyase, can protect against atherosclerosis and cardiac ischaemia–reperfusion injury.

          • H 2S regulates various pathophysiological functions via interaction with nitric oxide, activation of molecular signalling cascades, post-translational modification of proteins and control of redox-dependent responses.

          • Findings from clinical studies demonstrate that H 2S and its metabolites, including hydropersulfides and polysulfides, have substantial therapeutic potential for various forms of cardiovascular disease.

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          Most cited references223

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          H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase.

          Studies of nitric oxide over the past two decades have highlighted the fundamental importance of gaseous signaling molecules in biology and medicine. The physiological role of other gases such as carbon monoxide and hydrogen sulfide (H2S) is now receiving increasing attention. Here we show that H2S is physiologically generated by cystathionine gamma-lyase (CSE) and that genetic deletion of this enzyme in mice markedly reduces H2S levels in the serum, heart, aorta, and other tissues. Mutant mice lacking CSE display pronounced hypertension and diminished endothelium-dependent vasorelaxation. CSE is physiologically activated by calcium-calmodulin, which is a mechanism for H2S formation in response to vascular activation. These findings provide direct evidence that H2S is a physiologic vasodilator and regulator of blood pressure.
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            Myocardial reperfusion injury.

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              The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener.

              Hydrogen sulfide (H(2)S) has been traditionally viewed as a toxic gas. It is also, however, endogenously generated from cysteine metabolism. We attempted to assess the physiological role of H(2)S in the regulation of vascular contractility, the modulation of H(2)S production in vascular tissues, and the underlying mechanisms. Intravenous bolus injection of H(2)S transiently decreased blood pressure of rats by 12- 30 mmHg, which was antagonized by prior blockade of K(ATP) channels. H(2)S relaxed rat aortic tissues in vitro in a K(ATP) channel-dependent manner. In isolated vascular smooth muscle cells (SMCs), H(2)S directly increased K(ATP) channel currents and hyperpolarized membrane. The expression of H(2)S-generating enzyme was identified in vascular SMCs, but not in endothelium. The endogenous production of H(2)S from different vascular tissues was also directly measured with the abundant level in the order of tail artery, aorta and mesenteric artery. Most importantly, H(2)S production from vascular tissues was enhanced by nitric oxide. Our results demonstrate that H(2)S is an important endogenous vasoactive factor and the first identified gaseous opener of K(ATP) channels in vascular SMCs.
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                Author and article information

                Contributors
                chris.kevil@lsuhs.edu
                Journal
                Nat Rev Cardiol
                Nat Rev Cardiol
                Nature Reviews. Cardiology
                Nature Publishing Group UK (London )
                1759-5002
                1759-5010
                5 August 2022
                : 1-17
                Affiliations
                [1 ]GRID grid.411417.6, ISNI 0000 0004 0443 6864, Department of Pathology, , Louisiana State University Health Sciences Center, ; Shreveport, LA USA
                [2 ]GRID grid.411417.6, ISNI 0000 0004 0443 6864, Center of Excellence for Cardiovascular Diseases & Sciences, , Louisiana State University Health Sciences Center, ; Shreveport, LA USA
                [3 ]GRID grid.411417.6, ISNI 0000 0004 0443 6864, Department of Medicine, , Louisiana State University Health Sciences Center, ; Shreveport, LA USA
                [4 ]GRID grid.411417.6, ISNI 0000 0004 0443 6864, Department of Molecular and Cellular Physiology, , Louisiana State University Health Sciences Center, ; Shreveport, LA USA
                [5 ]GRID grid.411417.6, ISNI 0000 0004 0443 6864, Cellular Biology and Anatomy, , Louisiana State University Health Sciences Center, ; Shreveport, LA USA
                Author information
                http://orcid.org/0000-0002-4002-9671
                http://orcid.org/0000-0003-0863-7260
                Article
                741
                10.1038/s41569-022-00741-6
                9362470
                35931887
                11ce1478-b48f-4bc5-a34c-dd16514bb18c
                © Springer Nature Limited 2022

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 21 June 2022
                Categories
                Review Article

                cardiovascular diseases,cardiovascular biology
                cardiovascular diseases, cardiovascular biology

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