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Short Term Effects of Doxycycline on Matrix Metalloproteinases 2 and 9

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Abstract

Purpose

To investigate the short term effects of Doxycycline on MMP-2 and MMP-9.

Methods

Short term effects of Doxycycline (100 mg B.I.D.) on plasma levels of MMP-2 and MMP-9 were investigated in 20 healthy subjects; the effects of Doxy, Acetylsalicylic acid, Nitrates, and Enalapril on MMP-9 release from were assessed in isolated polymorphonuclear cells.

Results

In plasma, MMP-9 activity was reduced (−22%, 95% CI −32/−11; P = 0.002) starting at 12 h after doxy; in vitro, MMP-9 released from stimulated neutrophils was reduced by Doxy (−28%, 95% CI −43/−14; P = 0.001), inhibiting degranulation, and by nitrates (−52%, 95% CI −76/−28 P = 0.005), increasing three times both pro- and active-MMP-9 bound to neutrophils (P = 0.007 and 0.040, respectively).

Conclusions

Doxy decreases MMP-9 plasma levels by around 20%, within the first 12 h. The mechanism leading to such reduction seems due to the inhibition of PMN degranulation.

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References

  1. Birkedal-Hansen H. Proteolytic remodeling of extracellular matrix. Curr Opin Cell Biol. 1995;7:728–35.

    Article  PubMed  CAS  Google Scholar 

  2. Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, Baxter BT. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest. 2002;110:625–32.

    PubMed  CAS  Google Scholar 

  3. George SJ. Therapeutic potential of matrix metalloproteinase inhibitors in atherosclerosis. Expert Opin Investig Drugs. 2000;9:993–1007.

    Article  PubMed  CAS  Google Scholar 

  4. Pasterkamp G, Schoneveld AH, Hijnen DJ, de Kleijn DP, Teepen H, van der Wal AC, et al. Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteases 1, 2 and 9 in the human coronary artery. Atherosclerosis 2000;150:245–53.

    Article  PubMed  CAS  Google Scholar 

  5. Morishige K, Shimokawa H, Matsumoto Y, Eto Y, Uwatoku T, Abe K, et al. Overexpression of matrix metalloproteinase-9 promotes intravascular thrombus formation in porcine coronary arteries in vivo. Cardiovasc Res. 2003;57:572–85.

    Article  PubMed  CAS  Google Scholar 

  6. Woessner JFNH. Inhibition of the MMPs. In: Oxford University Press, editor. Matrix metalloproteinases and TIMPs. 1st ed. Oxford: Oxford University Press; 2000. p. 109–25.

    Google Scholar 

  7. Wojtowicz-Praga SM, Dickson RB, Hawkins MJ. Matrix metalloproteinase inhibitors. Invest New Drugs. 1997;15:61–75.

    Article  PubMed  CAS  Google Scholar 

  8. Burns FR, Stack MS, Gray RD, Paterson CA. Inhibition of purified collagenase from alkali-burned rabbit corneas. Invest Ophthalmol Vis Sci. 1989;30:1569–75.

    PubMed  CAS  Google Scholar 

  9. Nip LH, Uitto VJ, Golub LM. Inhibition of epithelial cell matrix metalloproteinases by tetracyclines. J Periodontal Res. 1993;28:379–85.

    Article  PubMed  CAS  Google Scholar 

  10. Prall AK, Longo GM, Mayhan WG, Waltke EA, Fleckten B, Thompson RW, et al. Doxycycline in patients with abdominal aortic aneurysms and in mice: comparison of serum levels and effect on aneurysm growth in mice. J Vasc Surg. 2002;35:923–9.

    Article  PubMed  Google Scholar 

  11. Mosorin M, Juvonen J, Biancari F, Satta J, Surcel HM, Leinonen M, et al. Use of doxycycline to decrease the growth rate of abdominal aortic aneurysms: a randomized, double-blind, placebo-controlled pilot study. J Vasc Surg. 2001;34:606–10.

    Article  PubMed  CAS  Google Scholar 

  12. Rentschler M, Baxter BT. Pharmacological approaches to prevent abdominal aortic aneurysm enlargement and rupture. Ann N Y Acad Sci. 2006;1085:39–46.

    Article  PubMed  CAS  Google Scholar 

  13. Fiotti N, Altamura N, Orlando C, Simi L, Reimers B, Pascotto P, et al. Metalloproteinases-2, -9 and TIMP-1 expression in stable and unstable coronary plaques undergoing PCI. Int J Cardiol. 2008;127:350–7.

    Article  PubMed  Google Scholar 

  14. Ronner E, Boersma E, Akkerhuis KM, Harrington RA, Lincoff AM, Deckers JW, et al. Patients with acute coronary syndromes without persistent ST elevation undergoing percutaneous coronary intervention benefit most from early intervention with protection by a glycoprotein IIb/IIIa receptor blocker. Eur Heart J. 2002;23:239–46.

    Article  PubMed  CAS  Google Scholar 

  15. Burrow JW, Koch JA, Chuang HH, Zhong W, Dean DD, Sylvia VL. Nitric oxide donors selectively reduce the expression of matrix metalloproteinases-8 and -9 by human diabetic skin fibroblasts. J Surg Res. 2007;140:90–8.

    Article  PubMed  CAS  Google Scholar 

  16. Dobrina A, Schwartz BR, Carlos TM, Ochs HD, Beatty PG, Harlan JM. CD11/CD18-independent neutrophil adherence to inducible endothelial-leucocyte adhesion molecules (E-LAM) in vitro. Immunology 1989;67:502–8.

    PubMed  CAS  Google Scholar 

  17. Bellavite P, Dri P, Della BV, Serra MC. The measurement of superoxide anion production by granulocytes In whole blood. A clinical test for the evaluation of phagocyte function and serum opsonic capacity. Eur J Clin Invest. 1983;13:363–8.

    Article  PubMed  CAS  Google Scholar 

  18. Riley GP, Curry V, DeGroot J, van El B, Verzijl N, Hazleman BL, et al. Matrix metalloproteinase activities and their relationship with collagen remodelling in tendon pathology. Matrix Biol. 2002;21:185–95.

    Article  PubMed  CAS  Google Scholar 

  19. Karlsson M, Hammers S, Nilsson-Ehle I, Malmborg AS, Wretlind B. Concentrations of doxycycline and penicillin G in sera and cerebrospinal fluid of patients treated for neuroborreliosis. Antimicrob Agents Chemother. 1996;40:1104–7.

    PubMed  CAS  Google Scholar 

  20. Gabler WL, Creamer HR. Suppression of human neutrophil functions by tetracyclines. J Periodontal Res. 1991;26:52–8.

    Article  PubMed  CAS  Google Scholar 

  21. Sorsa T, Ding Y, Salo T, Lauhio A, Teronen O, Ingman T, et al. Effects of tetracyclines on neutrophil, gingival, and salivary collagenases; a functional and western-blot assessment with special reference to their cellular sources in periodontal diseases. Ann N Y Acad Sci. 1994;732:112–31.

    Article  PubMed  CAS  Google Scholar 

  22. Smith GN Jr, Brandt KD, Hasty KA. Procollagenase is reduced to inactive fragments upon activation in the presence of doxycycline. Ann N Y Acad Sci. 1994;732:436–8.

    Article  PubMed  CAS  Google Scholar 

  23. Smith GN Jr, Brandt KD, Hasty KA. Activation of recombinant human neutrophil procollagenase in the presence of doxycycline results in fragmentation of the enzyme and loss of enzyme activity. Arthritis Rheum. 1996;39:235–44.

    Article  PubMed  CAS  Google Scholar 

  24. Baxter BT, Pearce WH, Waltke EA, Littooy FN, Hallett JW Jr, Kent KC, et al. Prolonged administration of doxycycline in patients with small asymptomatic abdominal aortic aneurysms: report of a prospective (Phase II) multicenter study. J Vasc Surg. 2002;36:1–12.

    Article  PubMed  Google Scholar 

  25. Brown DL, Desai KK, Vakili BA, Nouneh C, Lee HM, Golub LM. Clinical and biochemical results of the metalloproteinase inhibition with subantimicrobial doses of doxycycline to prevent acute coronary syndromes (MIDAS) pilot trial. Arterioscler Thromb Vasc Biol. 2004;24:733–8.

    Article  PubMed  CAS  Google Scholar 

  26. Ding R, McGuinness CL, Burnand KG, Sullivan E, Smith A. Matrix metalloproteinases in the aneurysm wall of patients treated with low-dose doxycycline. Vascular 2005;13:290–7.

    Article  PubMed  Google Scholar 

  27. Demestre M, Parkin-Smith G, Petzold A, Pullen AH. The pro and the active form of matrix metalloproteinase-9 is increased in serum of patients with amyotrophic lateral sclerosis. J Neuroimmunol. 2005;159:146–54.

    Article  PubMed  CAS  Google Scholar 

  28. Tao ZY, Cavasin MA, Yang F, Liu YH, Yang XP. Temporal changes in matrix metalloproteinase expression and inflammatory response associated with cardiac rupture after myocardial infarction in mice. Life Sci. 2004;74:1561–72.

    Article  PubMed  CAS  Google Scholar 

  29. Yang Y, Ma Y, Han W, Li J, Xiang Y, Liu F, et al. Age-related differences in postinfarct left ventricular rupture and remodeling. Am J Physiol Heart Circ Physiol. 2008;294:H1815–22.

    Article  PubMed  CAS  Google Scholar 

  30. Curci JA, Mao D, Bohner DG, Allen BT, Rubin BG, Reilly JM, et al. Preoperative treatment with doxycycline reduces aortic wall expression and activation of matrix metalloproteinases in patients with abdominal aortic aneurysms. J Vasc Surg. 2000;31:325–42.

    Article  PubMed  CAS  Google Scholar 

  31. Liu J, Xiong W, Baca-Regen L, Nagase H, Baxter BT. Mechanism of inhibition of matrix metalloproteinase-2 expression by doxycycline in human aortic smooth muscle cells. J Vasc Surg. 2003;38:1376–83.

    Article  PubMed  Google Scholar 

  32. Chen P, Yuan Y, Wang S, Zhan L, Xu J. Captopril, an angiotensin-converting enzyme inhibitor, attenuates the severity of acute pancreatitis in rats by reducing expression of matrix metalloproteinase 9. Tohoku J Exp Med. 2006;209:99–107.

    Article  PubMed  CAS  Google Scholar 

  33. Mehta JL, Chen J, Yu F, Li DY. Aspirin inhibits ox-LDL-mediated LOX-1 expression and metalloproteinase-1 in human coronary endothelial cells. Cardiovasc Res. 2004;64:243–9.

    Article  PubMed  CAS  Google Scholar 

  34. Vermeiren GL, Claeys MJ, Van Bockstaele D, Grobben B, Slegers H, Bossaert L, et al. Reperfusion injury after focal myocardial ischaemia: polymorphonuclear leukocyte activation and its clinical implications. Resuscitation 2000;45:35–61.

    Article  PubMed  CAS  Google Scholar 

  35. Fridman R, Toth M, Chvyrkova I, Meroueh SO, Mobashery S. Cell surface association of matrix metalloproteinase-9 (gelatinase B). Cancer Metastasis Rev. 2003;22:153–66.

    Article  PubMed  CAS  Google Scholar 

  36. Ischiropoulos H, Gow A. Pathophysiological functions of nitric oxide-mediated protein modifications. Toxicology 2005;208:299–303.

    Article  PubMed  CAS  Google Scholar 

  37. Axisa B, Loftus IM, Naylor AR, Goodall S, Jones L, Bell PR, et al. Prospective, randomized, double-blind trial investigating the effect of doxycycline on matrix metalloproteinase expression within atherosclerotic carotid plaques. Stroke 2002;33:2858–64.

    Article  PubMed  CAS  Google Scholar 

  38. Griffin MO, Jinno M, Miles LA, Villarreal FJ. Reduction of myocardial infarct size by doxycycline: a role for plasmin inhibition. Mol Cell Biochem. 2005;270:1–11.

    Article  PubMed  CAS  Google Scholar 

  39. Wu LM, Fan L, Chen LL. Precondition with doxycycline administration abates ischemia/reperfusion injury and reduces the expression of matrix metalloproteinase-1/9 in myocardium in rat in vivo. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2007;19:679–82.

    PubMed  CAS  Google Scholar 

  40. Hu J, Van den Steen PE, Dillen C, Opdenakker G. Targeting neutrophil collagenase/matrix metalloproteinase-8 and gelatinase B/matrix metalloproteinase-9 with a peptidomimetic inhibitor protects against endotoxin shock. Biochem Pharmacol. 2005;70:535–44.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are indebted with Dr. Daniela Bonifacio and Paola Pitacco for their excellent technical support. The study has been supported by a grant “Fondo Trieste 2006” to CG.

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Authors and Affiliations

  1. S. C. Clinica Medica Generale e Terapia Medica, Dipartimento di Scienze Cliniche, Morfologiche e Tecnologiche, Università degli Studi di Trieste, Strada di Fiume, 447, 34149, Trieste, Italy

    Nicola Fiotti, Nicola Altamura, Michèle Moretti, Stella Wassermann, Rossella Farra, Barbara Dapas, Lara Consoloni & Carlo Giansante

  2. ICGEB—International Center for Genetic Engineering and Biotechnology, AREA Science Park, Padriciano 99, 34012, Trieste, Italy

    Serena Zacchigna & Mauro Giacca

  3. Dipartimento di Scienze della Vita, Università degli Studi di Trieste, V. Giorgieri, 1, 34125, Trieste, Italy

    Gabriele Grassi

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  1. Nicola Fiotti
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  2. Nicola Altamura
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Correspondence to Nicola Fiotti.

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Fiotti, N., Altamura, N., Moretti, M. et al. Short Term Effects of Doxycycline on Matrix Metalloproteinases 2 and 9. Cardiovasc Drugs Ther 23, 153–159 (2009). https://doi.org/10.1007/s10557-008-6150-7

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  • DOI: https://doi.org/10.1007/s10557-008-6150-7

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