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Hydrogen sulfide protects against vascular remodeling from endothelial damage

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Abstract

Remodeling by its very nature implied synthesis and degradation of extracellular matrix (ECM) proteins. Although oxidative stress, matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) have been implicated in vascular remodeling, the differential role of MMPs versus TIMPs and oxidative stress in vascular remodeling was unclear. TIMP-3 induced vascular cell apoptosis, therefore, we hypothesized that during vascular injury TIMP-3, MMP-9 and -12 (elastin-degrading MMP) were increased, whereas MMP-2 (constitutive MMP) and TIMP-4 (cardioprotective TIMP) decreased. Because of the potent anti-oxidant, vasorelaxing, anti-hypertensive agent, hydrogen sulfide (H2S) was used to mitigate the vascular remodeling due to the differential expression of MMP and TIMP. Carotid artery injury was created by inserting a PE-10 catheter and rotating several times before pulling out. The insertion hole was sealed. Mice were grouped: wild type (WT), wild-type damaged artery (WTD), WT + NaHS (sodium hydrogen sulfide, precursor of H2S) treatment (30 µmol/L in drinking water/6 weeks) and WTD + NaHS treatment. Carotid arteries were analyzed for oxidative stress and remodeling, by measuring super oxide dismutase-1 (SOD1), p47 (NADPH oxidase subunit), nitrotyrosine, MMPs and TIMPs by in situ immunolabeling and by Western blot analyses. The results suggested robust increase in p47, nitrotyrosine, MMP-9, MMP-12, TIMP-3 and decrease in SOD1 and MMP-2 levels in the injured arteries. The treatment with H2S ameliorated these effects. We concluded that p47, TIMP-3, MMP-9 and -12 were increased where as SOD-1, MMP-2 and TIMP-4 were decreased in the injured arteries. The treatment with H2S mitigated the vascular remodeling by normalizing the levels of redox stress, MMPs and TIMPs.

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Abbreviations

AVF:

Aorta–venacava fistula.

BW:

Body weight

H2S:

Hydrogen sulfide

MMP:

Matrix metalloproteinase

NADPH:

Nicotinamide adenosine dihydrogenphosphate

NaHS:

Sodium hydrogen sulfide

p47:

Protein of 47 kDa

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

RTS:

Reactive thiol species

SOD:

Superoxide dismutase

STS:

Sodium thiosulfide

TIMP:

Tissue inhibitor of metalloproteinase

WT:

Wild type

WTD:

Wild-type damaged artery

References

  • Adhikari S, Bhatia M (2008) H2S-induced pancreatic acinar cell apoptosis is mediated via JNK and p38 MAP kinase. J Cell Mol Med 12:1374–1383

    Article  CAS  PubMed  Google Scholar 

  • Al-Chalabi A, Leigh PN (2000) Recent advances in amyotrophic lateral sclerosis. Curr Opin Neurol 13:397–405

    Article  CAS  PubMed  Google Scholar 

  • Ali MY, Ping CY, Mok YY, Ling L, Whiteman M, Bhatia M, Moore PK (2006) Regulation of vascular nitric oxide in vitro and in vivo; a new role for endogenous hydrogen sulphide? Br J Pharmacol 149:625–634

    Article  CAS  PubMed  Google Scholar 

  • Baker AH, Zaltsman AB, George SJ, Newby AC (1998) Divergent effects of tissue inhibitor of metalloproteinase-1, -2, or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro. TIMP-3 promotes apoptosis. J Clin Invest 101:1478–1487

    Article  CAS  PubMed  Google Scholar 

  • Baskar R, Li L, Moore PK (2007) Hydrogen sulfide-induces DNA damage and changes in apoptotic gene expression in human lung fibroblast cells. FASEB J 21:247–255

    Article  CAS  PubMed  Google Scholar 

  • Cao Y, Adhikari S, Ang AD, Moore PK, Bhatia M (2006) Mechanism of induction of pancreatic acinar cell apoptosis by hydrogen sulfide. Am J Physiol Cell Physiol 291:C503–C510

    Article  CAS  PubMed  Google Scholar 

  • Collin M, Anuar FB, Murch O, Bhatia M, Moore PK, Thiemermann C (2005) Inhibition of endogenous hydrogen sulfide formation reduces the organ injury caused by endotoxemia. Br J Pharmacol 146:498–505

    Article  CAS  PubMed  Google Scholar 

  • Conwit RA (2006) Preventing familial ALS: a clinical trial may be feasible but is an efficacy trial warranted? J Neurol Sci 251:1–2

    Article  PubMed  Google Scholar 

  • Elrod JW, Calvert JW, Morrison J, Doeller JE, Kraus DW, Tao L, Jiao X, Scalia R, Kiss L, Szabo C, Kimura H, Chow CW, Lefer DJ (2007) Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc Natl Acad Sci USA 104:15560–15565

    Article  CAS  PubMed  Google Scholar 

  • Hayden MR, Tyagi SC, Kolb L, Sowers JR, Khanna R (2005) Vascular ossification-calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxis-calcific uremic arteriolopathy: the emerging role of sodium thiosulfate. Cardiovasc Diabetol 4:4

    Article  PubMed  Google Scholar 

  • Henderson BC, Tyagi SC (2006) Oxidative mechanism and homeostasis of proteinase/antiproteinase in congestive heart failure. J Mol Cell Cardiol 41:959–962

    Article  CAS  PubMed  Google Scholar 

  • Herzlich BC, Lichstein E, Schulhoff N, Weinstock M, Pagala M, Ravindran K, Namba T, Nieto FJ, Stabler SP, Allen RH, Malinow MR (1996) Relationship among homocyst(e)ine, vitamin B-12 and cardiac disease in the elderly: association between vitamin B-12 deficiency and decreased left ventricular ejection fraction. J Nutr 126:1249S–1253S

    CAS  PubMed  Google Scholar 

  • Holven KB, Halvorsen B, Schulz H, Aukrust P, Ose L, Nenseter MS (2003) Expression of matrix metalloproteinase-9 in mononuclear cells of hyperhomocysteinaemic subjects. Eur J Clin Invest 33:555–560

    Article  CAS  PubMed  Google Scholar 

  • Hu LF, Wong PT, Moore PK, Bian JS (2007) Hydrogen sulfide attenuates lipopolysaccharide-induced inflammation by inhibition of p38 mitogen-activated protein kinase in microglia. J Neurochem 100:1121–1128

    Article  CAS  PubMed  Google Scholar 

  • Kartha GK, Moshal KS, Sen U, Joshua IG, Tyagi N, Steed MM, Tyagi SC (2008) Renal mitochondrial damage and protein modification in type-2 diabetes. Acta Diabetol 45:75–81

    Article  CAS  PubMed  Google Scholar 

  • Koenitzer JR, Isbell TS, Patel HD, Benavides GA, Dickinson DA, Patel RP, Darley-Usmar VM, Lancaster JR Jr, Doeller JE, Kraus DW (2007) Hydrogen sulfide mediates vasoactivity in an O2-dependent manner. Am J Physiol Heart Circ Physiol 292:H1953–H1960

    Article  CAS  PubMed  Google Scholar 

  • Li L, Bhatia M, Zhu YZ, Zhu YC, Ramnath RD, Wang ZJ, Anuar FB, Whiteman M, Salto-Tellez M, Moore PK (2005) Hydrogen sulfide is a novel mediator of lipopolysaccharide-induced inflammation in the mouse. FASEB J 19:1196–1198

    CAS  PubMed  Google Scholar 

  • Liu H, Bai XB, Shi S, Cao YX (2009) Hydrogen sulfide protects from intestinal ischaemia–reperfusion injury in rats. J Pharm Pharmacol 61:207–212

    Article  CAS  PubMed  Google Scholar 

  • Lominadze D, Roberts AM, Tyagi N, Moshal KS, Tyagi SC (2006) Homocysteine causes cerebrovascular leakage in mice. Am J Physiol Heart Circ Physiol 290:H1206–H1213

    Article  CAS  PubMed  Google Scholar 

  • Luo J (2005) The role of matrix metalloproteinases in the morphogenesis of the cerebellar cortex. Cerebellum 4:239–245

    Article  CAS  PubMed  Google Scholar 

  • Malemud CJ (2006) Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci 11:1696–1701

    Article  CAS  PubMed  Google Scholar 

  • Meissner M, Gille J, Kaufmann R (2006) Calciphylaxis: no therapeutic concepts for a poorly understood syndrome? J Dtsch Dermatol Ges 4:1037–1044

    Article  PubMed  Google Scholar 

  • Moshal KS, Tyagi N, Moss V, Henderson B, Steed M, Ovechkin A, Aru GM, Tyagi SC (2005) Early induction of matrix metalloproteinase-9 transduces signaling in human heart end stage failure. J Cell Mol Med 9:704–713

    Article  CAS  PubMed  Google Scholar 

  • Moshal KS, Sen U, Tyagi N, Henderson B, Steed M, Ovechkin AV, Tyagi SC (2006) Regulation of homocysteine-induced MMP-9 by ERK1/2 pathway. Am J Physiol Cell Physiol 290:C883–C891

    Article  CAS  PubMed  Google Scholar 

  • Moshal KS, Metreveli N, Frank I, Tyagi SC (2008) Mitochondrial MMP activation, dysfunction and arrhythmogenesis in hyperhomocysteinemia. Curr Vasc Pharmacol 6:84–92

    Article  CAS  PubMed  Google Scholar 

  • Raymond J, Lebel V, Ogoudikpe C, Metcalfe A, Chagnon M, Robledo O (2004) Recanalization of arterial thrombus, and inhibition with beta-radiation in a new murine carotid occlusion model: MRNA expression of angiopoietins, metalloproteinases, and their inhibitors. J Vasc Surg 40:1190–1198

    Article  PubMed  Google Scholar 

  • Rose P, Moore PK, Ming SH, Nam OC, Armstrong JS, Whiteman M (2005) Hydrogen sulfide protects colon cancer cells from chemopreventative agent beta-phenylethyl isothiocyanate induced apoptosis. World J Gastroenterol 11:3990–3997

    CAS  PubMed  Google Scholar 

  • Sen U, Herrmann M, Herrmann W, Tyagi SC (2007a) Synergism between AT1 receptor and hyperhomocysteinemia during vascular remodeling. Clin Chem Lab Med 45:1771–1776

    Article  CAS  PubMed  Google Scholar 

  • Sen U, Tyagi N, Kumar M, Moshal KS, Rodriguez WE, Tyagi SC (2007b) Cystathionine-beta-synthase gene transfer and 3-deazaadenosine ameliorate inflammatory response in endothelial cells. Am J Physiol 293:C1779–C1787

    Article  CAS  Google Scholar 

  • Sen U, Vacek TP, Hughes WM, Kumar M, Moshal KS, Tyagi N, Metreveli N, Hayden MR, Tyagi SC (2008) Cardioprotective role of sodium thiosulfate on chronic heart failure by modulating endogenous H2S generation. Pharmacology 82:201–213

    Article  CAS  PubMed  Google Scholar 

  • Sen U, Basu P, Abe OA, Givvimani S, Tyagi N, Metreveli N, Shah KS, Passmore JC, Tyagi SC (2009) Hydrogen sulfide ameliorates hyperhomocysteinemia-associated chronic renal failure. Am J Physiol Renal Physiol 297:F410–F419

    Article  CAS  PubMed  Google Scholar 

  • Shastry S, Moning L, Tyagi N, Steed M, Tyagi SC (2005) GABA receptors and nitric oxide ameliorate constrictive collagen remodeling in hyperhomocysteinemia. J Cell Physiol 205:422–427

    Article  CAS  PubMed  Google Scholar 

  • Shastry S, Tyagi N, Moshal KS, Lominadze D, Hayden MR, Tyagi SC (2006) GABA receptors ameliorate Hcy-mediated integrin shedding and constrictive collagen remodeling in microvascular endothelial cells. Cell Biochem Biophys 45:157–165

    Article  CAS  PubMed  Google Scholar 

  • Sivarajah A, Collino M, Yasin M, Benetti E, Gallicchio M, Mazzon E, Cuzzocrea S, Fantozzi R, Thiemermann C (2009) Anti-apoptotic and anti-inflammatory effects of hydrogen sulfide in a rat model of regional myocardial I/R. Shock 31:267–274

    Article  CAS  PubMed  Google Scholar 

  • Tisherman SA, Drabek T (2008) Hydrogen sulfide: metabolic mediator or toxic gas? Pediatr Crit Care Med 9:129–130

    Article  PubMed  Google Scholar 

  • Tyagi N, Sedoris KC, Steed M, Ovechkin AV, Moshal KS, Tyagi SC (2005a) Mechanisms of homocysteine-induced oxidative stress. Am J Physiol Heart Circ Physiol 289:H2649–H2656

    Article  CAS  PubMed  Google Scholar 

  • Tyagi SC, Lominadze D, Roberts AM (2005b) Homocysteine in microvascular endothelial cell barrier permeability. Cell Biochem Biophys 43:37–44

    Article  CAS  PubMed  Google Scholar 

  • Wagner F, Asfar P, Calzia E, Radermacher P, Szabo C (2009) Bench-to-bedside review: hydrogen sulfide–the third gaseous transmitter: applications for critical care. Crit Care 13:213

    Article  PubMed  Google Scholar 

  • Wald DS, Law M, Morris JK (2002) Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Br Med J 325:1202

    Article  Google Scholar 

  • Webb GD, Lim LH, Oh VM, Yeo SB, Cheong YP, Ali MY, El OR, Lee CN, Wong PS, Caleb MG, Salto-Tellez M, Bhatia M, Chan ES, Taylor EA, Moore PK (2008) Contractile and vasorelaxant effects of hydrogen sulfide and its biosynthesis in the human internal mammary artery. J Pharmacol Exp Ther 324:876–882

    Article  CAS  PubMed  Google Scholar 

  • Whiteman M, Armstrong JS, Chu SH, Jia-Ling S, Wong BS, Cheung NS, Halliwell B, Moore PK (2004) The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite ‘scavenger’? J Neurochem 90:765–768

    Article  CAS  PubMed  Google Scholar 

  • Whiteman M, Li L, Kostetski I, Chu SH, Siau JL, Bhatia M, Moore PK (2006) Evidence for the formation of a novel nitrosothiol from the gaseous mediators nitric oxide and hydrogen sulphide. Biochem Biophys Res Commun 343:303–310

    Article  CAS  PubMed  Google Scholar 

  • Yang G, Yang W, Wu L, Wang R (2007) H2S, endoplasmic reticulum stress, and apoptosis of insulin-secreting beta cells. J Biol Chem 282:16567–16576

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Zhi L, Moore PK, Bhatia M (2006) Role of hydrogen sulfide in cecal ligation and puncture-induced sepsis in the mouse. Am J Physiol Lung Cell Mol Physiol 290:L1193–L1201

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Zhi L, Moochhala S, Moore PK, Bhatia M (2007a) Hydrogen sulfide acts as an inflammatory mediator in cecal ligation and puncture-induced sepsis in mice by upregulating the production of cytokines and chemokines via NF-κB. Am J Physiol Lung Cell Mol Physiol 292:L960–L971

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Zhi L, Moochhala SM, Moore PK, Bhatia M (2007b) Endogenous hydrogen sulfide regulates leukocyte trafficking in cecal ligation and puncture-induced sepsis. J Leukoc Biol 82:894–905

    Article  CAS  PubMed  Google Scholar 

  • Zhang Z, Huang H, Liu P, Tang C, Wang J (2007c) Hydrogen sulfide contributes to cardioprotection during ischemia-reperfusion injury by opening K ATP channels. Can J Physiol Pharmacol 85:1248–1253

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Moochhala SM, Bhatia M (2008) Endogenous hydrogen sulfide regulates inflammatory response by activating the ERK pathway in polymicrobial sepsis. J Immunol 181:4320–4331

    CAS  PubMed  Google Scholar 

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Acknowledgments

A part of this study was supported by NIH Grants; HL-71010; HL-88012; and NS-51568.

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Authors and Affiliations

  1. Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY, 40202, USA

    Thomas P. Vacek, William Gillespie, Neetu Tyagi, Jonathan C. Vacek & Suresh C. Tyagi

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  1. Thomas P. Vacek
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  2. William Gillespie
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  3. Neetu Tyagi
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  4. Jonathan C. Vacek
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  5. Suresh C. Tyagi
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Correspondence to Suresh C. Tyagi.

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Vacek, T.P., Gillespie, W., Tyagi, N. et al. Hydrogen sulfide protects against vascular remodeling from endothelial damage. Amino Acids 39, 1161–1169 (2010). https://doi.org/10.1007/s00726-010-0550-2

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