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Doxycycline Prevents Acute Pulmonary Embolism-Induced Mortality and Right Ventricular Deformation in Rats

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Abstract

Purpose

Acute pulmonary embolism (APE) is a critical cardiopulmonary condition associated with right ventricular (RV) failure and death. While pharmacological inhibition of matrix metalloproteinases (MMPs) attenuated APE-induced hemodynamic alterations, no previous study has evaluated whether this approach decreases APE-induced mortality and RV deformation. We tested this hypothesis in rats.

Methods

Wistar rats received an intraperitoneal injection of 30 mg/kg doxycycline (or saline) and after 30 min a sterile suspension of 300 μm microsphere (21 mg/kg or saline) was injected into the tail vein. After 24 h, surviving animals were killed and the RVs were collected and used for histological and morphometric analyses. RV samples were also homogenized and assayed by SDS-polyacrilamide gel electrophoresis gelatin zymography to evaluate MMP-2 and MMP-9 activity. In situ zymography was carried out in RV to assess MMP activity and neutrophil accumulation in myocardial tissue was determined by myeloperoxidase activity measurement. Dihydroethidium was used to assess RV reactive oxygen species concentrations.

Results

APE caused 72.5 % mortality during the first hour of follow up. Pretreatment with doxycycline was associated with significant decrease in APE-induced mortality rate to 50 % (P < 0.05). Embolized animals showed significant RV dilation, and pretreatment with doxycycline blunted this alteration (P < 0.05). APE increased the number of RV neutrophils and MMP-9 levels (P < 0.05). Pretreatment with doxycycline blunted APE-induced increases in RV myocardial ROS concentrations and MMP gelatinolytic activity (both P < 0.05).

Conclusions

These findings show that MMP inhibition with doxycycline protects against APE-induced mortality and RV enlargement. These beneficial effects are probably due to attenuation of APE-induced oxidative stress and increases in ventricular proteolytic activity and suggest that doxycycline may have promising protective effects in patients with APE.

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References

  1. Wood KE. Major pulmonary embolism: Review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest. 2002;121:877–905.

    Article  PubMed  Google Scholar 

  2. Watts JA, Marchick MR, Kline JA. Right ventricular heart failure from pulmonary embolism: Key distinctions from chronic pulmonary hypertension. J Card Fail. 2010;16:250–9.

    Article  PubMed  Google Scholar 

  3. Lualdi JC, Goldhaber SZ. Right ventricular dysfunction after acute pulmonary embolism: Pathophysiologic factors, detection, and therapeutic implications. Am Heart J. 1995;130:1276–82.

    Article  PubMed  CAS  Google Scholar 

  4. Watts JA, Gellar MA, Obraztsova M, Kline JA, Zagorski J. Role of inflammation in right ventricular damage and repair following experimental pulmonary embolism in rats. Int J Exp Pathol. 2008;89:389–99.

    Article  PubMed  CAS  Google Scholar 

  5. Watts JA, Zagorski J, Gellar MA, Stevinson BG, Kline JA. Cardiac inflammation contributes to right ventricular dysfunction following experimental pulmonary embolism in rats. J Mol Cell Cardiol. 2006;41:296–307.

    Article  PubMed  CAS  Google Scholar 

  6. Zagorski J, Gellar MA, Obraztsova M, Kline JA, Watts JA. Inhibition of cinc-1 decreases right ventricular damage caused by experimental pulmonary embolism in rats. J Immunol. 2007;179:7820–6.

    PubMed  CAS  Google Scholar 

  7. Iwadate K, Doi M, Tanno K, et al. Right ventricular damage due to pulmonary embolism: Examination of the number of infiltrating macrophages. Forensic Sci Int. 2003;134:147–53.

    Article  PubMed  Google Scholar 

  8. Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc Res. 2004;61:481–97.

    Article  PubMed  CAS  Google Scholar 

  9. Hobeika MJ, Thompson RW, Muhs BE, Brooks PC, Gagne PJ. Matrix metalloproteinases in peripheral vascular disease. J Vasc Surg. 2007;45:849–57.

    Article  PubMed  Google Scholar 

  10. Schulz R. Intracellular targets of matrix metalloproteinase-2 in cardiac disease: Rationale and therapeutic approaches. Annu Rev Pharmacol Toxicol. 2007;47:211–42.

    Article  PubMed  CAS  Google Scholar 

  11. Chow AK, Cena J, Schulz R. Acute actions and novel targets of matrix metalloproteinases in the heart and vasculature. Br J Pharmacol. 2007;152:189–205.

    Article  PubMed  CAS  Google Scholar 

  12. Ali MA, Cho WJ, Hudson B, et al. Titin is a target of matrix metalloproteinase-2: Implications in myocardial ischemia/reperfusion injury. Circulation. 2010;122:2039–47.

    Article  PubMed  CAS  Google Scholar 

  13. Palei AC, Zaneti RA, Fortuna GM, Gerlach RF, Tanus-Santos JE. Hemodynamic benefits of matrix metalloproteinase-9 inhibition by doxycycline during experimental acute pulmonary embolism. Angiology. 2005;56:611–7.

    Article  PubMed  Google Scholar 

  14. Neto-Neves EM, Dias-Junior CA, Rizzi E, et al. Metalloproteinase inhibition protects against cardiomyocyte injury during experimental acute pulmonary thromboembolism. Crit Care Med. 2011;39:349–56.

    Article  PubMed  CAS  Google Scholar 

  15. Griffin MO, Ceballos G, Villarreal FJ. Tetracycline compounds with non-antimicrobial organ protective properties: Possible mechanisms of action. Pharmacol Res. 2011;63:102–7.

    Article  PubMed  CAS  Google Scholar 

  16. Souza-Costa DC, Figueiredo-Lopes L, Alves-Filho JC, et al. Protective effects of atorvastatin in rat models of acute pulmonary embolism: Involvement of matrix metalloproteinase-9. Crit Care Med. 2007;35:239–45.

    Article  PubMed  CAS  Google Scholar 

  17. Jacob-Ferreira AL, Palei AC, Cau SB, et al. Evidence for the involvement of matrix metalloproteinases in the cardiovascular effects produced by nicotine. Eur J Pharmacol. 2010;627:216–22.

    Article  PubMed  CAS  Google Scholar 

  18. Rizzi E, Castro MM, Prado CM, et al. Matrix metalloproteinase inhibition improves cardiac dysfunction and remodeling in 2-kidney, 1-clip hypertension. J Card Fail. 2010;16:599–608.

    Article  PubMed  CAS  Google Scholar 

  19. Sousa-Santos O, Neto-Neves EM, Ferraz KC, et al. Antioxidant treatment protects against matrix metalloproteinase activation and cardiomyocyte injury during acute pulmonary thromboembolism. Naunyn Schmiedebergs Arch Pharmacol. 2012;385:685–96.

    Article  PubMed  CAS  Google Scholar 

  20. Rizzi E, Castro MM, Ceron CS, et al. Tempol inhibits tgf-beta and mmps upregulation and prevents cardiac hypertensive changes. Int J Cardiol 2011

  21. Sanchez O, Trinquart L, Colombet I, et al. Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: A systematic review. Eur Heart J. 2008;29:1569–77.

    Article  PubMed  Google Scholar 

  22. Faurschou M, Borregaard N. Neutrophil granules and secretory vesicles in inflammation. Microbes Infect. 2003;5:1317–27.

    Article  PubMed  CAS  Google Scholar 

  23. Rouet-Benzineb P, Buhler JM, Dreyfus P, et al. Altered balance between matrix gelatinases (mmp-2 and mmp-9) and their tissue inhibitors in human dilated cardiomyopathy: Potential role of mmp-9 in myosin-heavy chain degradation. Eur J Heart Fail. 1999;1:337–52.

    Article  PubMed  CAS  Google Scholar 

  24. Uzuelli JA, Dias-Junior CA, Tanus-Santos JE. Severity dependent increases in circulating cardiac troponin i and mmp-9 concentrations after experimental acute pulmonary thromboembolism. Clin Chim Acta. 2008;388:184–8.

    Article  PubMed  CAS  Google Scholar 

  25. Fortuna GM, Figueiredo-Lopes L, Dias-Junior CA, Gerlach RF, Tanus-Santos JE. A role for matrix metalloproteinase-9 in the hemodynamic changes following acute pulmonary embolism. Int J Cardiol. 2007;114:22–7.

    Article  PubMed  Google Scholar 

  26. Souza-Costa DC, Zerbini T, Palei AC, Gerlach RF, Tanus-Santos JE. L-arginine attenuates acute pulmonary embolism-induced increases in lung matrix metalloproteinase-2 and matrix metalloproteinase-9. Chest. 2005;128:3705–10.

    Article  PubMed  CAS  Google Scholar 

  27. Fernandez-Patron C, Radomski MW, Davidge ST. Vascular matrix metalloproteinase-2 cleaves big endothelin-1 yielding a novel vasoconstrictor. Circ Res. 1999;85:906–11.

    Article  PubMed  CAS  Google Scholar 

  28. Fernandez-Patron C, Zouki C, Whittal R, et al. Matrix metalloproteinases regulate neutrophil-endothelial cell adhesion through generation of endothelin-1[1–32]. FASEB J. 2001;15:2230–40.

    Article  PubMed  CAS  Google Scholar 

  29. Tanus-Santos JE, Gordo WM, Udelsmann A, Cittadino MH, Moreno Jr H. Nonselective endothelin-receptor antagonism attenuates hemodynamic changes after massive pulmonary air embolism in dogs. Chest. 2000;118:175–9.

    Article  PubMed  CAS  Google Scholar 

  30. Tanus-Santos JE, Gordo WM, Udelsmann A, Moreno Jr H. The hemodynamic effects of endothelin receptor antagonism during a venous air infusion in dogs. Anesth Analg. 2000;90:102–6.

    Article  PubMed  CAS  Google Scholar 

  31. Kraus RL, Pasieczny R, Lariosa-Willingham K, et al. Antioxidant properties of minocycline: Neuroprotection in an oxidative stress assay and direct radical-scavenging activity. J Neurochem. 2005;94:819–27.

    Article  PubMed  CAS  Google Scholar 

  32. Castro MM, Tanus-Santos JE, Gerlach RF. Matrix metalloproteinases: Targets for doxycycline to prevent the vascular alterations of hypertension. Pharmacol Res. 2011;64:567–72.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We gratefully acknowledge to the excellent technical support of Maria Elena Riul. This study was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP-Brazil) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Brazil).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirao Preto, SP, Brazil

    Stefany B. A. Cau, Renan C. Barato & Jose E. Tanus-Santos

  2. Department of Pathology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil

    Mara R. Celes & Marcos A. Rossi

  3. Department of Pathology, Institute of Tropical Pathology and Public Health, Federal University of Goias, Goiania, GO, Brazil

    Mara R. Celes

  4. Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil

    Jaqueline J. Muniz

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  1. Stefany B. A. Cau
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  2. Renan C. Barato
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  6. Jose E. Tanus-Santos
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Correspondence to Jose E. Tanus-Santos.

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Cau, S.B.A., Barato, R.C., Celes, M.R. et al. Doxycycline Prevents Acute Pulmonary Embolism-Induced Mortality and Right Ventricular Deformation in Rats. Cardiovasc Drugs Ther 27, 259–267 (2013). https://doi.org/10.1007/s10557-013-6458-9

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  • DOI: https://doi.org/10.1007/s10557-013-6458-9

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