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Hydrogen sulfide and the vasculature: a novel vasculoprotective entity and regulator of nitric oxide bioavailability?

Whiteman M, Moore PK - J. Cell. Mol. Med. (2009)

Bottom Line: Hydrogen sulfide (H(2)S) is a well known and pungent toxic gas that has recently been shown to be synthesised in man from the amino acids cystathionine, homocysteine and cysteine by at least two distinct enzymes; cystathionine-gamma-lyase and cystathionine-beta-synthase.Therefore, in this review we summarize the mechanisms by which H(2)S has been proposed to regulate blood pressure and cardiac function, discuss the mechanistic discrepancies reported in the literature as well as the therapeutic potential of H(2)S.We also highlight the complex interaction of H(2)S with nitric oxide in regulating cardiovascular function in health and disease.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedical and Clinical Science, Peninsula Medical School, St Luke's Campus, Exeter, UK. matt.whiteman@pms.ac.uk

ABSTRACT
Hydrogen sulfide (H(2)S) is a well known and pungent toxic gas that has recently been shown to be synthesised in man from the amino acids cystathionine, homocysteine and cysteine by at least two distinct enzymes; cystathionine-gamma-lyase and cystathionine-beta-synthase. In the past few years, H(2)S has emerged as a novel and increasingly important mediator in the cardiovascular system but delineating the precise physiology and pathophysiology of H(2)S is proving to be complex and difficult to unravel with disparate findings reported with cell types, tissue types and animal species reported. Therefore, in this review we summarize the mechanisms by which H(2)S has been proposed to regulate blood pressure and cardiac function, discuss the mechanistic discrepancies reported in the literature as well as the therapeutic potential of H(2)S. We also examine the methods of H2S detection in biological fluids, processes for H(2)S removal and discuss the reported blood levels of H(2)S in man and animal models of cardiovascular pathology. We also highlight the complex interaction of H(2)S with nitric oxide in regulating cardiovascular function in health and disease.

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Major Pathways of H2S synthesis in vivo. H2S is synthesized from the amino acids L-cysteine and L-cystathionine by one of two enzymes (depending on cell type), cystathion-ine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). Aminooxyacetate and propargyl-glycine (PAG) are commonly used inhibitors of CBS and CSE activity, respectively. The most prominent source of H2S in the vasculature is CSE. Removal of H2S is thought to occur via oxidation to sulfate (SO42−), sulfite (SO32–) and thiosulfate (S2O32−), scavenging by methemoglobin (MetHb) or methylation by enzymes such as thiolmethyltransferase (TMT) and rhodanese to form methanethiol (CH4S) and dimethylsulfide (CH3SCH3).
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fig01: Major Pathways of H2S synthesis in vivo. H2S is synthesized from the amino acids L-cysteine and L-cystathionine by one of two enzymes (depending on cell type), cystathion-ine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). Aminooxyacetate and propargyl-glycine (PAG) are commonly used inhibitors of CBS and CSE activity, respectively. The most prominent source of H2S in the vasculature is CSE. Removal of H2S is thought to occur via oxidation to sulfate (SO42−), sulfite (SO32–) and thiosulfate (S2O32−), scavenging by methemoglobin (MetHb) or methylation by enzymes such as thiolmethyltransferase (TMT) and rhodanese to form methanethiol (CH4S) and dimethylsulfide (CH3SCH3).

Mentions: H2S is rapidly emerging as an important gaseous mediator in the vasculature. In sharp contrast to nitric oxide, and as one would expect from an emerging field of research, its vascular effects, its mechanism of action as well as the processes controlling the regulation of its synthesis are poorly understood. As with nitric oxide, H2S is a highly lipophilic molecule and freely penetrates cells of all types. Whether or not H2S and nitric oxide exert their effects in vivo independently or in tandem is currently not known but a growing body of literature is highly suggestive of H2S involvement in the regulation of nitric oxide mediated signalling events and/or vice versa. The bulk of endogenous H2S synthesis in mammalian tissues appears to be from the pyridoxal-5’-phosphate-dependent enzymes cystathionine-γ-lyase (CSE; E.C. 4.4.1.1) and cystathionine-β-synthase (CBS; E.C. 4.2.1.22) and by analogy with NOS use amino acids as substrates; in this case cystathionine, cysteine and homocysteine (summarized in Fig. 1). H2S may also be formed in vivo from the enzymatic desulfuration of β-mercaptopyruvate derived from cysteine transamination [12] although it is currently uncertain how this pathway contributes to the levels of H2S reported in mammalian tissues (see below). In should be noted at this point that in aqueous solution H2S is weakly acidic (pKa at 37°C, 6.76) and dissociates to form two dissociation states; the hydrosulfide anion (HS−), pKa 7.04 and sulfide anion (S2-), pKa 11.96 according to the following sequential reactions


Hydrogen sulfide and the vasculature: a novel vasculoprotective entity and regulator of nitric oxide bioavailability?

Whiteman M, Moore PK - J. Cell. Mol. Med. (2009)

Major Pathways of H2S synthesis in vivo. H2S is synthesized from the amino acids L-cysteine and L-cystathionine by one of two enzymes (depending on cell type), cystathion-ine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). Aminooxyacetate and propargyl-glycine (PAG) are commonly used inhibitors of CBS and CSE activity, respectively. The most prominent source of H2S in the vasculature is CSE. Removal of H2S is thought to occur via oxidation to sulfate (SO42−), sulfite (SO32–) and thiosulfate (S2O32−), scavenging by methemoglobin (MetHb) or methylation by enzymes such as thiolmethyltransferase (TMT) and rhodanese to form methanethiol (CH4S) and dimethylsulfide (CH3SCH3).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3822510&req=5

fig01: Major Pathways of H2S synthesis in vivo. H2S is synthesized from the amino acids L-cysteine and L-cystathionine by one of two enzymes (depending on cell type), cystathion-ine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). Aminooxyacetate and propargyl-glycine (PAG) are commonly used inhibitors of CBS and CSE activity, respectively. The most prominent source of H2S in the vasculature is CSE. Removal of H2S is thought to occur via oxidation to sulfate (SO42−), sulfite (SO32–) and thiosulfate (S2O32−), scavenging by methemoglobin (MetHb) or methylation by enzymes such as thiolmethyltransferase (TMT) and rhodanese to form methanethiol (CH4S) and dimethylsulfide (CH3SCH3).
Mentions: H2S is rapidly emerging as an important gaseous mediator in the vasculature. In sharp contrast to nitric oxide, and as one would expect from an emerging field of research, its vascular effects, its mechanism of action as well as the processes controlling the regulation of its synthesis are poorly understood. As with nitric oxide, H2S is a highly lipophilic molecule and freely penetrates cells of all types. Whether or not H2S and nitric oxide exert their effects in vivo independently or in tandem is currently not known but a growing body of literature is highly suggestive of H2S involvement in the regulation of nitric oxide mediated signalling events and/or vice versa. The bulk of endogenous H2S synthesis in mammalian tissues appears to be from the pyridoxal-5’-phosphate-dependent enzymes cystathionine-γ-lyase (CSE; E.C. 4.4.1.1) and cystathionine-β-synthase (CBS; E.C. 4.2.1.22) and by analogy with NOS use amino acids as substrates; in this case cystathionine, cysteine and homocysteine (summarized in Fig. 1). H2S may also be formed in vivo from the enzymatic desulfuration of β-mercaptopyruvate derived from cysteine transamination [12] although it is currently uncertain how this pathway contributes to the levels of H2S reported in mammalian tissues (see below). In should be noted at this point that in aqueous solution H2S is weakly acidic (pKa at 37°C, 6.76) and dissociates to form two dissociation states; the hydrosulfide anion (HS−), pKa 7.04 and sulfide anion (S2-), pKa 11.96 according to the following sequential reactions

Bottom Line: Hydrogen sulfide (H(2)S) is a well known and pungent toxic gas that has recently been shown to be synthesised in man from the amino acids cystathionine, homocysteine and cysteine by at least two distinct enzymes; cystathionine-gamma-lyase and cystathionine-beta-synthase.Therefore, in this review we summarize the mechanisms by which H(2)S has been proposed to regulate blood pressure and cardiac function, discuss the mechanistic discrepancies reported in the literature as well as the therapeutic potential of H(2)S.We also highlight the complex interaction of H(2)S with nitric oxide in regulating cardiovascular function in health and disease.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedical and Clinical Science, Peninsula Medical School, St Luke's Campus, Exeter, UK. matt.whiteman@pms.ac.uk

ABSTRACT
Hydrogen sulfide (H(2)S) is a well known and pungent toxic gas that has recently been shown to be synthesised in man from the amino acids cystathionine, homocysteine and cysteine by at least two distinct enzymes; cystathionine-gamma-lyase and cystathionine-beta-synthase. In the past few years, H(2)S has emerged as a novel and increasingly important mediator in the cardiovascular system but delineating the precise physiology and pathophysiology of H(2)S is proving to be complex and difficult to unravel with disparate findings reported with cell types, tissue types and animal species reported. Therefore, in this review we summarize the mechanisms by which H(2)S has been proposed to regulate blood pressure and cardiac function, discuss the mechanistic discrepancies reported in the literature as well as the therapeutic potential of H(2)S. We also examine the methods of H2S detection in biological fluids, processes for H(2)S removal and discuss the reported blood levels of H(2)S in man and animal models of cardiovascular pathology. We also highlight the complex interaction of H(2)S with nitric oxide in regulating cardiovascular function in health and disease.

Show MeSH
Related in: MedlinePlus