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Antioxidant effect of doxycycline decreases MMP activity and blood pressure in SHR

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Abstract

Increased matrix metalloproteinase (MMP) levels are involved in vascular remodeling of hypertension. In this study, we hypothesized that doxycycline (a MMP inhibitor) could exert antioxidant effects, reverse establish vascular remodeling, and lower blood pressure in spontaneously hypertensive rats (SHR). SHR and Wistar–Kyoto rats received either doxycycline at 30 mg/kg/day by gavage or vehicle. Systolic blood pressure (SBP) was assessed weekly by tail cuff. After 5 weeks of treatment, morphologic changes in the aortic wall were studied in hematoxylin/eosin sections. MMP activity and expression were determined by in situ zymography using DQ gelatin and immunofluorescence for MMP-2. Dihydroethidium was used to evaluate aortic reactive oxygen species (ROS) production by fluorescence microscopy. Doxycycline reduced SBP by 25 mmHg. However, the antihypertensive effects were not associated with significant reversal of hypertension-induced vascular hypertrophy. SHR showed increased aortic MMP-2 levels which co-localized with higher aortic MMP activity and ROS levels, and all those biochemical alterations associated with hypertension were blunted by treatment with doxycycline. These results show that MMP inhibition with doxycycline in SHR with established hypertension resulted in antioxidant effects, lower gelatinolytic activity, and antihypertensive effects which were not associated with reversal of hypertension-induced vascular remodeling.

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References

  1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ (2003) Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 42(6):1206–1252

    Article  CAS  PubMed  Google Scholar 

  2. Castro MM, Tanus-Santos JE (2013) Inhibition of matrix metalloproteinases (MMPs) as a potential strategy to ameliorate hypertension-induced cardiovascular alterations. Curr Drug Targets 14(3):335–343

    CAS  PubMed  Google Scholar 

  3. Rizzoni D, Porteri E, Boari GE, De Ciuceis C, Sleiman I, Muiesan ML, Castellano M, Miclini M, Agabiti-Rosei E (2003) Prognostic significance of small-artery structure in hypertension. Circulation 108(18):2230–2235

    Article  PubMed  Google Scholar 

  4. Castro MM, Tanus-Santos JE, Gerlach RF (2011) Matrix metalloproteinases: targets for doxycycline to prevent the vascular alterations of hypertension. Pharmacol Res 64(6):567–572

    Article  CAS  PubMed  Google Scholar 

  5. Galis ZS, Khatri JJ (2002) Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 90(3):251–262

    CAS  PubMed  Google Scholar 

  6. Rodrigues SF, Tran ED, Fortes ZB, Schmid-Schonbein GW (2010) Matrix metalloproteinases cleave the beta2-adrenergic receptor in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 299(1):H25–H35

    Article  CAS  PubMed  Google Scholar 

  7. Ferraz KC, Sousa-Santos O, Neto-Neves EM, Rizzi E, Muniz JJ, Gerlach RF, Tanus-Santos JE (2013) Recombinant human matrix metalloproteinase-2 impairs cardiovascular beta-adrenergic responses. Basic Clin Pharmacol Toxicol 112(2):103–109

    Article  CAS  PubMed  Google Scholar 

  8. Castro MM, Rizzi E, Figueiredo-Lopes L, Fernandes K, Bendhack LM, Pitol DL, Gerlach RF, Tanus-Santos JE (2008) Metalloproteinase inhibition ameliorates hypertension and prevents vascular dysfunction and remodeling in renovascular hypertensive rats. Atherosclerosis 198(2):320–331

    Article  CAS  PubMed  Google Scholar 

  9. Guimaraes DA, Rizzi E, Ceron CS, Oliveira AM, Oliveira DM, Castro MM, Tirapelli CR, Gerlach RF, Tanus-Santos JE (2011) Doxycycline dose-dependently inhibits MMP-2-mediated vascular changes in 2K1C hypertension. Basic Clin Pharmacol Toxicol 108(5):318–325

    Article  CAS  PubMed  Google Scholar 

  10. Bouvet C, Gilbert LA, Girardot D, deBlois D, Moreau P (2005) Different involvement of extracellular matrix components in small and large arteries during chronic NO synthase inhibition. Hypertension 45(3):432–437

    Article  CAS  PubMed  Google Scholar 

  11. Watts SW, Rondelli C, Thakali K, Li X, Uhal B, Pervaiz MH, Watson RE, Fink GD (2007) Morphological and biochemical characterization of remodeling in aorta and vena cava of DOCA-salt hypertensive rats. Am J Physiol Heart Circ Physiol 292(5):H2438–H2448

    Article  CAS  PubMed  Google Scholar 

  12. Flamant M, Placier S, Dubroca C, Esposito B, Lopes I, Chatziantoniou C, Tedgui A, Dussaule JC, Lehoux S (2007) Role of matrix metalloproteinases in early hypertensive vascular remodeling. Hypertension 50(1):212–218

    Article  CAS  PubMed  Google Scholar 

  13. Hao L, Du M, Lopez-Campistrous A, Fernandez-Patron C (2004) Agonist-induced activation of matrix metalloproteinase-7 promotes vasoconstriction through the epidermal growth factor-receptor pathway. Circ Res 94(1):68–76

    Article  CAS  PubMed  Google Scholar 

  14. Tayebjee MH, Nadar S, Blann AD, Gareth Beevers D, MacFadyen RJ, Lip GY (2004) Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in hypertension and their relationship to cardiovascular risk and treatment: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Am J Hypertens 17(9):764–769

    CAS  PubMed  Google Scholar 

  15. Fontana V, Silva PS, Izidoro-Toledo TC, Biagi C, Oliveira EB, Gerlach RF, Tanus-Santos JE (2012) Comprehensive evaluation of the effects of enalapril on matrix metalloproteinases levels in hypertension. Cardiovasc Drugs Ther 26(6):511–519

    Article  CAS  PubMed  Google Scholar 

  16. Fontana V, Silva PS, Belo VA, Antonio RC, Ceron CS, Biagi C, Gerlach RF, Tanus-Santos JE (2011) Consistent alterations of circulating matrix metalloproteinases levels in untreated hypertensives and in spontaneously hypertensive rats: a relevant pharmacological target. Basic Clin Pharmacol Toxicol 109(2):130–137

    Article  CAS  PubMed  Google Scholar 

  17. Fontana V, Silva PS, Gerlach RF, Tanus-Santos JE (2012) Circulating matrix metalloproteinases and their inhibitors in hypertension. Clin Chim Acta 413(7–8):656–662

    Article  CAS  PubMed  Google Scholar 

  18. Lee HM, Ciancio SG, Tuter G, Ryan ME, Komaroff E, Golub LM (2004) Subantimicrobial dose doxycycline efficacy as a matrix metalloproteinase inhibitor in chronic periodontitis patients is enhanced when combined with a non-steroidal anti-inflammatory drug. J Periodontol 75(3):453–463

    Article  CAS  PubMed  Google Scholar 

  19. Van Wart HE, Birkedal-Hansen H (1990) The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci USA 87(14):5578–5582

    Article  PubMed  Google Scholar 

  20. Ramamurthy NS, Vernillo AT, Greenwald RA, Lee HM, Sorsa T, Golub LM, Rifkin BR (1993) Reactive oxygen species activate and tetracyclines inhibit rat osteoblast collagenase. J Bone Miner Res 8(10):1247–1253

    Article  CAS  PubMed  Google Scholar 

  21. Castro MM, Rizzi E, Ceron CS, Guimaraes DA, Rodrigues GJ, Bendhack LM, Gerlach RF, Tanus-Santos JE (2012) Doxycycline ameliorates 2K-1C hypertension-induced vascular dysfunction in rats by attenuating oxidative stress and improving nitric oxide bioavailability. Nitric Oxide 26(3):162–168

    Article  CAS  PubMed  Google Scholar 

  22. Palei AC, Zaneti RA, Fortuna GM, Gerlach RF, Tanus-Santos JE (2005) Hemodynamic benefits of matrix metalloproteinase-9 inhibition by doxycycline during experimental acute pulmonary embolism. Angiology 56(5):611–617

    Article  PubMed  Google Scholar 

  23. Ceron CS, Castro MM, Rizzi E, Montenegro MF, Fontana V, Salgado MC, Gerlach RF, Tanus-Santos JE (2010) Spironolactone and hydrochlorothiazide exert antioxidant effects and reduce vascular matrix metalloproteinase-2 activity and expression in a model of renovascular hypertension. Br J Pharmacol 160(1):77–87

    Article  CAS  PubMed  Google Scholar 

  24. Martinez ML, Castro MM, Rizzi E, Fernandes K, Demacq C, Bendhack LM, Gerlach RF, Tanus-Santos JE (2008) Lercanidipine reduces matrix metalloproteinase-2 activity and reverses vascular dysfunction in renovascular hypertensive rats. Eur J Pharmacol 591(1–3):224–230

    Article  CAS  PubMed  Google Scholar 

  25. Castro MM, Rizzi E, Rodrigues GJ, Ceron CS, Bendhack LM, Gerlach RF, Tanus-Santos JE (2009) Antioxidant treatment reduces matrix metalloproteinase-2-induced vascular changes in renovascular hypertension. Free Radic Biol Med 46(9):1298–1307

    Article  CAS  PubMed  Google Scholar 

  26. Ceron CS, Rizzi E, Guimaraes DA, Martins-Oliveira A, Cau SB, Ramos J, Gerlach RF, Tanus-Santos JE (2012) Time course involvement of matrix metalloproteinases in the vascular alterations of renovascular hypertension. Matrix Biol 31(4):261–270

    Article  CAS  PubMed  Google Scholar 

  27. Cau SB, Guimaraes DA, Rizzi E, Ceron CS, Souza LL, Tirapelli CR, Gerlach RF, Tanus-Santos JE (2011) Pyrrolidine dithiocarbamate down-regulates vascular matrix metalloproteinases and ameliorates vascular dysfunction and remodelling in renovascular hypertension. Br J Pharmacol 164(2):372–381

    Article  CAS  PubMed  Google Scholar 

  28. Frohlich ED (1986) Is the spontaneously hypertensive rat a model for human hypertension? J Hypertens Suppl 4(3):S15–S19

    CAS  PubMed  Google Scholar 

  29. deBlois D, Tea BS, Than VD, Tremblay J, Hamet P (1997) Smooth muscle apoptosis during vascular regression in spontaneously hypertensive rats. Hypertension 29(1 Pt 2):340–349

    Article  CAS  PubMed  Google Scholar 

  30. Pires PW, Rogers CT, McClain JL, Garver HS, Fink GD, Dorrance AM (2011) Doxycycline, a matrix metalloprotease inhibitor, reduces vascular remodeling and damage after cerebral ischemia in stroke-prone spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 301(1):H87–H97

    Article  CAS  PubMed  Google Scholar 

  31. Lai HC, Yeh YC, Ting CT, Lee WL, Lee HW, Wang LC, Wang KY, Lai HC, Wu A, Liu TJ (2010) Doxycycline suppresses doxorubicin-induced oxidative stress and cellular apoptosis in mouse hearts. Eur J Pharmacol 644(1–3):176–187

    Article  CAS  PubMed  Google Scholar 

  32. Griffin MO, Fricovsky E, Ceballos G, Villarreal F (2010) Tetracyclines: a pleitropic family of compounds with promising therapeutic properties. Review of the literature. Am J Physiol Cell Physiol 299(3):C539–C548

    Article  CAS  PubMed  Google Scholar 

  33. Castier Y, Ramkhelawon B, Riou S, Tedgui A, Lehoux S (2009) Role of NF-kappaB in flow-induced vascular remodeling. Antioxid Redox Signal 11(7):1641–1649

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Fundação de Aparo a Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). The authors thank Prof. Valdo J. D. Silva for providing the rats for this study.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, Ribeirao Preto, SP, Brazil

    Raquel C. Antonio, Carla S. Ceron, Elen Rizzi & Jose E. Tanus-Santos

  2. Department of Internal Medicine, Faculty of Medicine of Ribeirao Preto, Ribeirao Preto, SP, Brazil

    Eduardo B. Coelho

  3. Department of Morphology and Physiology, Dental School of Ribeirao Preto, University of São Paulo, Av. do Cafe S/N, Ribeirão Preto, SP, 14040-904, Brazil

    Raquel F. Gerlach

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  1. Raquel C. Antonio
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  2. Carla S. Ceron
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  5. Jose E. Tanus-Santos
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Correspondence to Raquel F. Gerlach.

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Antonio, R.C., Ceron, C.S., Rizzi, E. et al. Antioxidant effect of doxycycline decreases MMP activity and blood pressure in SHR. Mol Cell Biochem 386, 99–105 (2014). https://doi.org/10.1007/s11010-013-1848-7

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  • DOI: https://doi.org/10.1007/s11010-013-1848-7

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