Published online before print November 26, 2008, doi: 10.1161/ATVBAHA.108.180190
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© 2009 American Heart Association, Inc.
Editorials |
Is H2S a Stinky Remedy for Atherosclerosis?
From Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada.
Correspondence to Rui Wang, Lakehead University, Thunder Bay, 955 Oliver Rd, Ontario P7B5E1, Canada. E-mail rwang{at}lakeheadu.ca
Atherosclerosis is a complex and chronic pathological state that adversely affects the structure of blood vessels. Vascular inflammation, endothelial damage, smooth muscle cell migration, foam cell accumulation, and lipid and cholesterol deposition contribute to different stages of plaque formation in large and medium-sized blood vessels. The consequential narrowing and stiffening of blood vessels restricts blood circulation and increases plaque thrombogenicity. Pathogenic causes that lead to these pathological changes in atherosclerosis have always been the center of attention, but we have not yet cleared the cloud on this issue.
See accompanying article on page 173
An ancient problem may have an ancient solution. A disease older than the history of mankind, atherosclerosis affects the health of various species in a much more profound fashion than other types of cardiovascular problems. Taking the fish as a case in point, whereas heart failure and hypertension are nonissues with them, fishes spontaneously develop atherosclerosis in their natural habitat regardless of what are on their menu. Even more ancient than the origin of atherosclerosis, production of hydrogen sulfide (H2S) gas by living organisms can be traced far back before the evolvement of the vascular system. Bacteria and archaea produce and use H2S as the essential element for their survival and proliferation. In eukaryotes, H2S is produced under the enzymatic actions of 2 pyridoxal-5'-phosphate-dependent enzymes, cystathionine beta–synthase (CBS) and cystathionine 
-lyase (CSE).1 Importantly, CSE is a major H2S-producing enzyme in the cardiovascular system.2
Recent advance in our understanding of the biological importance of endogenous H2S has shed light on the potential use of this ancient gasotransmitter to deal with atherosclerosis. First, H2S inhibits smooth muscle cell proliferation, one major event in atherosclerosis. Yang et al2 previously reported that, after inhibiting endogenous H2S production by DL-propargyglycine (PPG) pretreatment or knocking down endogenous CSE gene by short interfering RNA approach, H2S at 50 to 100 µmol/L induces apoptosis of human aorta smooth muscle cells (SMCs).3 Without inhibiting endogenous H2S production, exogenously applied H2S at 100 µmol/L had little effect on SMC apoptosis. The importance of the interaction between exogenous and endogenous H2S is thus indicated. Second, H2S inhibits homocysteine-induced vascular damage. Homocysteine is a key amino acid in regulating cellular levels of cysteine, methionine, and sulfur. Accumulation of homocysteine in the plasma, termed hyperhomocysteinemia, is considered to be an established risk factor for atherosclerosis. Dietary supplementation with methionine and homocysteine induced hyperhomocysteinemia which promoted early atherosclerosis in apolipoprotein E–deficient (apoE–/–) mice.4 The development of hyperhomocysteinemia in CSE gene knockout mice has been recently shown.5 It has also been demonstrated that low levels of NaHS (30 or 50 µmol/L) protected rat aortic SMCs from homocysteine-induced cytoxicity and reactive oxygen species, leading to improved cell viability.6 Third, H2S reduces atherogenesis. H2S inhibited atherogenic modification of purified LDL induced by hypochlorite in vitro, as measured by apolipoprotein alterations.7 Meng et al reported that during neointimal formation induced by balloon injury in rats,8 CSE expression was reduced and endogenous production of H2S decreased. Rescue of the injured artery with NaHS not only reversed the reduced endothelium-dependent vasorelaxation, but also significantly inhibited neointima formation of the balloon-injured carotid arteries.8
The report by Wang et al in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology adds a new twist in searching for the direct correlation of H2S and atherosclerosis.9 They found that treatment of apoE–/– mice with NaHS resulted in reduced atherosclerotic plaque, whereas inhibition of CSE activity in apoE–/– mice with PPG enlarged plaque size. By promoting adhesion of inflammatory cells to the endothelium, intracellular adhesion molecule-1 (ICAM-1) may be one of the causative factors for atherosclerosis as its level is significantly higher in human atherosclerotic plaques. Wang et al attributed the antiatherosclerotic effect of NaHS on apoE–/– mice to the reduced ICAM-1 level in circulation and lowered expression of ICAM-1 in aortic endothelial cells.9
The excitement brought by the observation of Wang et al9 is beyond the therapeutic value of NaHS in atherosclerosis, which can be traced back to previous reports.3,8 It also proposes challenges and questions. Essential and curious enough for the root of pathogenesis of atherosclerosis is whether abnormality of CSE/H2S system is the cause or consequence of the disease. While showing a marginal decrease in H2S level in plasma from apoE–/– mice having advanced atherosclerosis, basal levels of H2S and CSE protein expression before the manifestation of atherosclerosis in apoE–/– mice were not determined.9 What is even more perplexing is the aortic production rate of H2S and aortic CSE expression level in apoE–/– mice.9 Decreased H2S production rate should reflect decreased CSE activity or expression. The decreased H2S production rate, however, as reported by Wang et al, contradicts with the increased CSE mRNA expression in aortic atherosclerotic tissues,9 which cannot be readily explained by an assumed "positive feedback" mechanism.
Interactions between SMCs and endothelial cells are key to atherosclerosis development. Wang et al proposed that H2S produced by SMCs may carry a signal to endothelial cells, thereby altering the production of ICAM-1 and affecting endothelial integrity.9 This is an interesting concept and worth further comment. Expression of CSE mRNA was initially localized in vascular SMCs, not endothelial cells2; however, immunoblot analysis had not been done to detect CSE protein in endothelial cells in earlier studies. As our understanding of the tissue- and species-specific expression of CSE mRNA and proteins deepened, as well as the availability of more specific and sensitive antibodies against CSE that target different CSE protein epitopes, the cellular location of CSE in blood vessel has been better resolved. A recent study by Yang et al presented clear evidence that mouse blood vessels express CSE protein both in vascular smooth muscle and endothelium layers.5 Cultured HUVECs also express CSE protein and produce H2S.5 Even in the report by Wang et al, immunopositive staining for CSE seems also obvious in the endothelial layer of mouse aortic tissues from wild-type and apoE–/– mice (see Wang et al,9 Figure 2). It is therefore likely that H2S produced by endothelial cells has a direct autocrinal effect on endothelial cells to regulate ICAM-1 production.
Although a causative role of H2S in the pathogenesis of atherosclerosis is still open for debate and inconsistencies have been encountered, it is clear from this novel study by Wang et al that H2S can be used as an effective therapeutic intervention for atherosclerosis in apoE–/– mice.9 Stinky but healthy, H2S therapy appears to be a good trade-off. Consumption of garlic, preserved bean curd (stinky tofu), or preserved egg (thousand year’s egg) all increase the production of H2S. But before you put these on the dinner table, pause a while to hold your breath. If there were a "positive feedback" mechanism between H2S and CSE expression as proposed by Wang et al in this issue, application of exogenous H2S to atherosclerotic patients would lead to inhibited CSE expression and decreased endogenous H2S level. Would be this a good news for the prognosis of atherosclerotic patients? Let’s pause even longer and investigate further the correlation between H2S and atherosclerosis.
It ain’t done till it’s done.
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Acknowledgments |
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Disclosures
None.
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References |
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 Top References |
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1. Wang R. Two’s company, three’s a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J. 2002; 16: 1792–1798.
2. Zhao W, Zhang J, Lu Y, Wang R. The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener. EMBO J. 2001; 20: 6008–6016.[CrossRef][Medline] [Order article via Infotrieve]
3. Yang G, Sun X, Wang R. Hydrogen sulfide-induced apoptosis of human aorta smooth muscle cells via the activation of mitogen-activated protein kinases and caspase-3. FASEB J. 2004; 18: 1782–1784.
4. Zhou J, Møller J, Danielsen CC, Bentzon J, Ravn HB, Austin RC, Falk E. Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2001; 21: 1470–1476.
5. Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, Meng Q, Mustafa AK, Mu W, Zhang S, Snyder SH, Wang R. H2S as a physiologic vasorelaxant: Hypertension in mice with deletion of cystathionine gamma-lyase. Science. 2008; 322: 587–590.
6. Yan S-K, Chang T, Wang H, Wu L, Wang L, Meng QH. Effects of hydrogen sulfide on homocysteine-induced oxidative stress in vascular smooth muscle cells. Biochem Biophysic Res Commu. 2006; 351: 485–491.[CrossRef]
7. Laggner H, Muellner MK, Schreier S, Sturm B, Hermann M, Exner M, Gmeiner BM, Kapiotis S. Hydrogen sulphide: a novel physiological inhibitor of LDL atherogenic modification by HOCl. Free Radic Res. 2007; 41: 741–747.[CrossRef][Medline] [Order article via Infotrieve]
8. Meng QH, Yang G, Yang W, Jiang B, Wu L, Wang R. Protective effect of hydrogen sulfide 7 on balloon injury induced neointima hyperplasia in rat carotid arteries. Am J Pathol. 2007; 170: 1406–1414.
9. Wang Y, Zhao X, Jin H, Wei H, Li W, Bu D, Tang X, Ren Y, Tang C, Du J. The role of hydrogen sulfide in the development of atherosclerotic lesions in apolipoprotein-E knockout mice. Arterioscler Thromb Vasc Biol. 2009; 29: 173–179.
Related Article:
Arterioscler Thromb Vasc Biol 2009 29: 173-179.
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