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Thromb Haemost 2005; 94(03): 639-645
DOI: 10.1160/TH05-03-0174
Cell Signalling and Vessel Remodelling
Schattauer GmbH

Ethanol inhibits pulse pressure-induced vascular smooth muscle cell migration by differentially modulating plasminogen activator inhibitor type 1, matrix metalloproteinase-2 and -9

John P. Cullen
2   Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
,
Shariq Sayeed
2   Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
,
Youngrin Kim
2   Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
,
Nicholas G. Theodorakis
2   Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
,
James V. Sitzmann
2   Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
,
Paul A. Cahill
1   Vascular Health Research Centre, Dublin City University, Dublin, Ireland
,
Eileen M. Redmond
2   Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
› Author Affiliations Financial support:This work was supported in part by grants from the National Institutes of Health (AA-12610 to EMR, DK47067 to JVS) and by grants from the Wellcome Trust and the Health Research Board of Ireland (PAC). JPC is the recipient of a Scientist Development Grant from the American Heart Association.
Further Information

Publication History

Received: 09 March 2005

Accepted after major revision: 24 May 2005

Publication Date:
07 December 2017 (online)

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Summary

We investigated the effect of ethanol on the pulse pressure-induced expression of PAI-1 and MMP-2/9 in human smooth muscle cells (SMC). Human SMC were exposed to static or pulse pressure (25 mL/min; pulse pressure 106/50 mm Hg) conditions for 24 h in the absence or presence of ethanol (0.1-100 mM). SMC migration was then measured byTranswell migration assay. SMC exposed to pulse pressure demonstrated a significant increase in PAI-1 mRNA and protein expression (∼4-fold and ∼3-fold) concomitant with a 3- and 8-fold increase in MMP-2 and MMP-9 protein, respectively. Ethanol dose-dependently inhibited the pulse pressure-induced SMC migration with complete inhibition observed at 20 mM. There was no effect of ethanol on basal PAI-1 or MMP-2/9 in SMC under static conditions. However, ethanol significantly enhanced the pulse pressure- induced PAI-1 mRNA and protein expression (2.2±0.52 fold and 2.5±0.27 fold, for 10 mM), respectively. In contrast, ethanol dose-dependently inhibited the pulse pressure-induced increases in MMP-9 protein and pro-MMP-9 activity and to a lesser extent MMP-2 mRNA and protein and pro-MMP-2 activity, with significant inhibition observed at 1 mM. These data provide a molecular mechanism mediating the inhibitory effect of ethanol on pulse-pressure-induced SMC migration and may be relevant to the cardioprotective effects of ethanol in vivo.

Keywords

Cell migration - smooth muscle cells - proteases/inhibitors - alcohol - hemodynamic forces
 

  • References

  • 1 Rimm EB, Klatsky A, Grobbee D. et al. Review of moderate alcohol consumption and reduced risks of coronary heart disease: Is the effect due to beer, wine or spirits?. Br Med J 1996; 312: 731-6.
    CrossrefPubMedGoogle Scholar
  • 2 Doll R, Peto R, Hall E. et al. Mortality in relation to the consumption of alcohol: 13 year observation on male British doctors.. Br Med J 1994; 309: 911-8.
    CrossrefPubMedGoogle Scholar
  • 3 Hoffmann PL, Tabakoff B. Ethanol and guanine nucleotide binding proteins: A selective interaction.. FASEB J 1990; 4: 2612-22.
    CrossrefPubMedGoogle Scholar
  • 4 Hoek JB, Higashi K. Effects of alcohol on polyphosphoinositide- mediated intracellular signaling.. Ann NY Acad Sci 1991; 625: 375-87.
    CrossrefPubMedGoogle Scholar
  • 5 Merritt R, Guruge BL, Miller DD. et al. Moderate alcohol feeding attenuates postinjury vascular cell proliferation in rabbit angioplasty models.. J Cardiovasc Pharm 1997; 30: 19-25.
    CrossrefPubMedGoogle Scholar
  • 6 Liu MW, Anderson PG, Luo JF. et al. Local delivery of ethanol inhibits intimal hyperplasia in pig coronary arteries after balloon injury.. Circulation 1997; 96: 2295-301.
    CrossrefPubMedGoogle Scholar
  • 7 Ross R. The pathogenesis of atherosclerosis: A perspective for the 1990’s.. Nature 1993; 362: 801-9.
    CrossrefPubMedGoogle Scholar
  • 8 Raines EW, Ross R. Smooth muscle cells and the pathogenesis of the lesions of atherosclerosis.. Br Heart J 1993; 69: S30-S37.
    CrossrefPubMedGoogle Scholar
  • 9 Kenagy RD, Vergel S, Mattsson E. et al. The role of plasminogen, plasminogen activators and matrix metalloproteinases in primate arterial smooth muscle migration.. Arterioscler Thromb Vasc Biol 1996; 16: 1373-82.
    CrossrefPubMedGoogle Scholar
  • 10 Cho A, Reidy MA. MMP-9 is necessary for the regulation of smooth muscle cell replication and migration after arterial injury.. Circ Res 2002; 91: 845-51.
    CrossrefPubMedGoogle Scholar
  • 11 Carmeliet P, Moons L, Lijen R. et al. Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: a gene targeting and gene transfer study in mice.. Circulation 1997; 96: 3180-91.
    CrossrefPubMedGoogle Scholar
  • 12 Hasenstab D, Lea H, Clowes AW. Local plasminogen activator inhibitor type 1 overexpression in rat carotid artery enhances thrombosis and endothelial regeneration while inhibiting intimal thickening.. Arterioscler Thromb Vasc Biol 2000; 20: 846-52.
    CrossrefPubMedGoogle Scholar
  • 13 Strauss BH, Lau HK, Bowman KA. et al. Plasma urokinase antigen and plasminogen activator inhibitor- 1 antigen levels predict angiographic coronary restenosis.. Circulation 1999; 100: 1616-22.
    CrossrefPubMedGoogle Scholar
  • 14 Stefansson S, Lawrence DA. The serpin PAI-1 inhibits cell migration by blocking integrin αvβ3 binding to vitronectin.. Nature 1996; 383: 441-3.
    CrossrefPubMedGoogle Scholar
  • 15 Carmeliet P, Moons L, Lijen R. et al. Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: a gene targeting and gene transfer study in mice.. Circulation 1997; 96: 3180-91.
    CrossrefPubMedGoogle Scholar
  • 16 Lijnen HR. Plasmin and matrix metalloproteinases in vascular remodeling.. Thromb Haemost. 2001; 86: 324-33.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Dollery CM, McEwan JR, Henney AM. Matrix metalloproteinases and cardiovascular disease.. Circ Res 1995; 77: 863-8.
    CrossrefPubMedGoogle Scholar
  • 18 Zempo N, Kenagy RD, Au T. et al. Matrix metalloproteinases of vascular wall cells are increased in balloon- injured rat carotid.. J Vasc Surg 1994; 20: 209-17.
    CrossrefPubMedGoogle Scholar
  • 19 Benedeck MP, Zempo N, Clowes AW. et al. Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat.. Circ Res 1994; 75: 539-45.
    CrossrefPubMedGoogle Scholar
  • 20 Forough R, Koyama N, Hasentab D. et al. Overexpression of tissue inhibitor of matrix metalloproteinase- 1 inhibits vascular smooth muscle cell functions in vitro and in vivo.. Circ Res 1996; 79: 812-20.
    CrossrefPubMedGoogle Scholar
  • 21 Cappadona C, Redmond EM, Theodorakis NG. et al. Phenotype dictates the growth response of vascular smooth muscle cells to pulse pressure in vitro.. Exp Cell Res 1999; 250: 174-86.
    CrossrefPubMedGoogle Scholar
  • 22 Heistad DD, Lopez JA, Baumbach GL. Hemodynamic determinants of vascular changes in hypertension and atherosclerosis.. Hypertension 1991; 17: 7-11.
    PubMedGoogle Scholar
  • 23 Redmond EM, Cahill PA, Hirsch M. et al. Effect of pulse pressure on vascular smooth musce cell migration: the role of urokinase and matrix metalloproteinase.. Thromb Haemost 1999; 81: 293-300.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Redmond EM, Cullen JP, Cahill PA. et al. Endothelial cells inhibit flow-induced smooth muscle cell migration: role of plasminogen activator inhibitor-1.. Circulation 2001; 103: 597-603.
    CrossrefPubMedGoogle Scholar
  • 25 Cullen JP, Nicholl SM, Sayeed S. et al. Plasminogen activator inhibitor-1 deficiency enhances flow-induced smooth muscle cell migration.. Thromb Res 2004; 114: 57-65.
    CrossrefPubMedGoogle Scholar
  • 26 Hendrickson RJ, Okada SS, Cahill PA. et al. Ethanol inhibits basal and flow-induced vascular smooth muscle cell migration in vitro.. J Surg Res 1999; 84: 64-70.
    CrossrefPubMedGoogle Scholar
  • 27 Hendrickson RJ, Cahill PA, McKillop IH. et al. Ethanol inhibits mitogen activated protein kinase activity and growth of vascular smooth muscle cells in vitro.. Eur J Pharmacol 1998; 362: 251-9.
    CrossrefPubMedGoogle Scholar
  • 28 Sayeed S, Cullen JP, Coppage M. et al. Ethanol differentially modulates the expression and activity of cell cycle regulatory proteins in rat aortic smooth muscle cells.. Eur J Pharmacol 2002; 445: 163-70.
    CrossrefPubMedGoogle Scholar
  • 29 Thun MJ, Peto R, Lopez AD. et al. Alcohol consumption and mortality among middle-aged and elderly U.S. adults.. N Engl J Med 1997; 337: 1705-14.
    CrossrefPubMedGoogle Scholar
  • 30 Hendriks HF, Veenstra J, Velthuis-te Wierik EJ. et al. Effect of moderate dose of alcohol with evening meal on fibrinolytic factors.. BMJ 1994; 308: 1003-6.
    CrossrefPubMedGoogle Scholar
  • 31 Grenett HE, Aikens ML, Tabengwa EM. et al. Ethanol downregulates transcription of the PAI-1 gene in cultured human endothelial cells.. Thromb Res 2000; 97: 247-55.
    CrossrefPubMedGoogle Scholar
  • 32 Booyse FM, Aikens ML, Grenett HE. Endothelial cell fibrinolysis: transcriptional regulation of fibrinolytic protein gene expression (t-PA, u-PA, and PAI-1) by low alcohol.. Alcohol Clin Exp Res. 1999; 23: 1119-24.
    PubMedGoogle Scholar
  • 33 Proia RR, Nelson PR, Mulligan-Kehoe MJ. et al. The effect of endothelial cell overexpression of plasminogen activator inhibitor-1 on smooth muscle cell migration.. J Vasc Surg 2002; 36: 164-71.
    CrossrefPubMedGoogle Scholar
  • 34 Tanaka S, Koyama H, Ichii T. et al. Fibrillar collagen regulation of plasminogen activator inhibitor-1 is involved in altered smooth muscle cell migration.. Arterioscler Thromb Vasc Biol 2002; 22: 1573-8.
    CrossrefPubMedGoogle Scholar
  • 35 Zhu Y, Farrehi PM, Fay WP. Plasminogen activator inhibitor type 1 enhances neointima formation after oxidative vascular injury in atherosclerosis-prone mice.. Circulation 2001; 103: 3105-10.
    CrossrefPubMedGoogle Scholar
  • 36 Kjoller L, Kanse SM, Kirkegaard T. et al. PAI-1 represses integrin- and vitronectin-mediated cell migration independently of its function as an inhibitor of plasminogen activation.. Exp Cell Res 1997; 232: 420-9.
    CrossrefPubMedGoogle Scholar
  • 37 Sillanaukee P, Kalela A, Seppa K. et al. Matrix metalloproteinase-9 is elevated in serum of alcohol abusers.. Eur J Clin Invest 2002; 32: 225-9.
    CrossrefPubMedGoogle Scholar
  • 38 Partridge CR, Sampson HW, Forough R. Longterm alcohol consumption increases matrix metalloproteinase- 2 activity in rat aorta.. Life Sci 1999; 65: 1395-402.
    CrossrefPubMedGoogle Scholar
  • 39 Asanuma K, Magid R, Johnson C. et al. Uniaxial strain upregulates matrix-degrading enzymes produced by human vascular smooth muscle cells.. Am J Physiol Heart Circ Physiol 2003; 284: H1778-84.
    CrossrefPubMedGoogle Scholar
  • 40 Mason DP, Kenagy RD, Hasenstab D. et al. Matrix metalloproteinase-9 overexpression enhances vascular smooth muscle cell migration and alters remodeling in the injured rat carotid artery.. Circ Res 1999; 85: 1179-85.
    CrossrefPubMedGoogle Scholar
  • 41 Johnson C, Galis ZS. Matrix metalloproteinase-2 and –9 differentially regulate smooth muscle cell migration and cell-mediated collagen organization.. Arterioscler Thromb Vasc Biol 2004; 24: 54-60.
    CrossrefPubMedGoogle Scholar