Molecular and Cellular Biochemistry

, Volume 300, Issue 1–2, pp 159–169 | Cite as

Effects of timed administration of doxycycline or methylprednisolone on post-myocardial infarction inflammation and left ventricular remodeling in the rat heart

  • Ricardo A. Garcia
  • Katrina V. Go
  • Francisco J. Villarreal
Original Paper


The development of strategies to ameliorate post-myocardial infarction (MI) remodeling and improve function continues to be an area of clinical importance. Use of steroids for this purpose is controversial since the effects of timed treatment on relevant inflammatory, biochemical and structure/function endpoints are unclear. In a previous report, we demonstrated that use of doxycycline pre-treatment improves post-MI remodeling and passive left ventricular (LV) function. However, the effects of timed doxycyline post-MI treatment are unknown. To examine these issues, we performed a study using a rat MI model. Animals were administered one of the following: doxycycline (DOX), the corticosteroid methylprednisolone (MP), or aqueous vehicle. Treatment was given early, short-term (at time of MI to 24 h post-MI) or late, long term (2–7 days post-MI). Animals were sacrificed at 3, 7 or 42 days post-surgery. We assessed LV hemodynamics, pressure–volume, and pressure–scar strains, histomorphometry, inflammation via measurements of myeloperoxidase activity, and matrix metalloproteinase (MMP) activity. Late MP treatment yielded a robust right-shifted pressure–volume curve, which was accompanied by increased scar strains. Late DOX treatment yielded reduced average heart weight and size and preserved scar thickness. DOX treatment did not suppress inflammation, which contrasts with the suppressive effects of MP. Use of early or late MP yielded increased MMP activity in infarcted and non-infarcted regions. Early and late treatment with DOX yielded infarct–associated MMP activity levels comparable to those of vehicle–treated animals. In conclusion, results indicate that late use of MP yields adverse post-MI structure/function outcomes that correlate with suppression of inflammation and increased MMP activity. These observations contrast with those of DOX, in particular, late treatment where improved outcomes were observed in LV structure and were accompanied by the lack of suppression of inflammation.


Left Ventricular Pressure Late Treatment Infarcted Wall Adverse Left Ventricular Remodel Scar Region 



This study was supported by NIH grants HL-43617 to Dr. F. Villarreal and HL-07444 to Dr. R. Garcia. We thank Dr. Paul Juneau for his insightful review of statistical analyses used in this report.


  1. 1.
    Pfeffer MA, Braunwald E (1990) Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation 81:1161–72PubMedGoogle Scholar
  2. 2.
    Hobbs RE (2004) Management of decompensated heart failure. Am J Ther 11:473–9PubMedCrossRefGoogle Scholar
  3. 3.
    Nian M, Lee P, Khaper N, Liu P (2004) Inflammatory cytokines and post-myocardial infarction remodeling. Circ Res 94:1543–53PubMedCrossRefGoogle Scholar
  4. 4.
    Silverman HS, Pfeifer MP (1987) Relation between use of anti-inflammatory agents and left ventricular free wall rupture during acute myocardial infarction. Am J Cardiol 59:363–4PubMedCrossRefGoogle Scholar
  5. 5.
    Hammerman H, Schoen FJ, Braunwald E, Kloner RA (1984) Drug-induced expansion of infarct: morphologic and functional correlations. Circulation 69:611–7PubMedGoogle Scholar
  6. 6.
    Van Kerckhoven R, Kalkman EA, Saxena PR, Schoemaker RG (2000) Altered cardiac collagen and associated changes in diastolic function of infarcted rat hearts. Cardiovasc Res 46:316–23PubMedCrossRefGoogle Scholar
  7. 7.
    Mannisi JA, Weisman HF, Bush DE, Dudeck P, Healy B (1987) Steroid administration after myocardial infarction promotes early infarct expansion. A study in the rat. J Clin Invest 79:1431–9PubMedGoogle Scholar
  8. 8.
    LeGal YM, Morrissey LL (1990) Methylprednisolone interventions in myocardial infarction: a controversial subject. Can J Cardiol 6:405–10PubMedGoogle Scholar
  9. 9.
    Libby P, Maroko PR, Bloor CM, Sobel BE, Braunwald E (1973) Reduction of experimental myocardial infarct size by corticosteroid administration. J Clin Invest 52:599–607PubMedGoogle Scholar
  10. 10.
    Spath JA Jr, Lane DL, Lefer AM (1974) Protective action of methylprednisolone on the myocardium during experimental myocardial ischemia in the cat. Circ Res 35:44–51PubMedGoogle Scholar
  11. 11.
    Hafezi-Moghadam A, Simoncini T, Yang Z, Limbourg FP, Plumier JC, Rebsamen MC, Hsieh CM, Chui DS, Thomas KL, Prorock AJ, Laubach VE, Moskowitz MA, French BA, Ley K, Liao JK (2002) Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med 8:473–9PubMedCrossRefGoogle Scholar
  12. 12.
    Valen G, Kawakami T, Tahepold P, Dumitrescu A, Lowbeer C, Vaage J (2000) Glucocorticoid pretreatment protects cardiac function and induces cardiac heat shock protein 72. Am J Physiol Heart Circ Physiol 279:H836–43PubMedGoogle Scholar
  13. 13.
    Frangogiannis NG, Smith CW, Entman ML (2002) The inflammatory response in myocardial infarction. Cardiovasc Res 53:31–47PubMedCrossRefGoogle Scholar
  14. 14.
    Entman ML, Youker KA, Frangogiannis N, Lakshminarayanan V, Nossuli T, Evans A, Kurrelmeyer K, Mann DL, Smith CW (2000) Is inflammation good for the ischemic heart–perspectives beyond the ordinary. Z Kardiol 89 Suppl 9:IX/82–7Google Scholar
  15. 15.
    Jugdutt BI (2003) Ventricular remodeling after infarction and the extracellular collagen matrix: when is enough enough? Circulation 108:1395–403PubMedCrossRefGoogle Scholar
  16. 16.
    Dovi JV, He LK, DiPietro LA (2003) Accelerated wound closure in neutrophil-depleted mice. J Leukoc Biol 73:448–55PubMedCrossRefGoogle Scholar
  17. 17.
    Sapadin AN, Fleischmajer R (2006) Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol 54:258–65PubMedCrossRefGoogle Scholar
  18. 18.
    Golub LM, Sorsa T, Lee HM, Ciancio S, Sorbi D, Ramamurthy NS, Gruber B, Salo T, Konttinen YT (1995) Doxycycline inhibits neutrophil (PMN)-type matrix metalloproteinases in human adult periodontitis gingiva. J Clin Periodontol 22:100–9PubMedCrossRefGoogle Scholar
  19. 19.
    Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN, Patel IR, Abramson SB (1996) A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci U S A 93:14014–9PubMedCrossRefGoogle Scholar
  20. 20.
    Hoyt JC, Ballering J, Numanami H, Hayden JM, Robbins RA (2006) Doxycycline modulates nitric oxide production in murine lung epithelial cells. J Immunol 176:567–72PubMedGoogle Scholar
  21. 21.
    Schmidt HH, Walter U (1994) NO at work. Cell 78:919–25PubMedCrossRefGoogle Scholar
  22. 22.
    Robbins RA, Hadeli K, Nelson D, Sato E, Hoyt JC (2000) Nitric oxide, peroxynitrite, and lower respiratory tract inflammation. Immunopharmacology 48:217–21PubMedCrossRefGoogle Scholar
  23. 23.
    Cross RK, Wilson KT (2003) Nitric oxide in inflammatory bowel disease. Inflamm Bowel Dis 9:179–89PubMedCrossRefGoogle Scholar
  24. 24.
    Scarabelli TM, Knight R, Stephanou A, Townsend P, Chen-Scarabelli C, Lawrence K, Gottlieb R, Latchman D, Narula J (2006) Clinical implications of apoptosis in ischemic myocardium. Curr Probl Cardiol 31:181–264PubMedCrossRefGoogle Scholar
  25. 25.
    Scarabelli TM, Stephanou A, Pasini E, Gitti G, Townsend P, Lawrence K, Chen-Scarabelli C, Saravolatz L, Latchman D, Knight R, Gardin J (2004) Minocycline inhibits caspase activation and reactivation, increases the ratio of XIAP to smac/DIABLO, and reduces the mitochondrial leakage of cytochrome C and smac/DIABLO. J Am Coll Cardiol 43:865–74PubMedCrossRefGoogle Scholar
  26. 26.
    Cheung PY, Sawicki G, Wozniak M, Wang W, Radomski MW, Schulz R (2000) Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart. Circulation 101:1833–9PubMedGoogle Scholar
  27. 27.
    Sawicki G, Leon H, Sawicka J, Sariahmetoglu M, Schulze CJ, Scott PG, Szczesna-Cordary D, Schulz R (2005) Degradation of myosin light chain in isolated rat hearts subjected to ischemia-reperfusion injury: a new intracellular target for matrix metalloproteinase-2. Circulation 112:544–52PubMedCrossRefGoogle Scholar
  28. 28.
    Villarreal FJ, Griffin M, Omens J, Dillmann W, Nguyen J, Covell J (2003) Early short-term treatment with doxycycline modulates post-infarction left ventricular remodeling. Circulation 108:1487–92PubMedCrossRefGoogle Scholar
  29. 29.
    Garcia RA, Pantazatos DP, Gessner CR, Go KV, Woods VL Jr, Villarreal FJ (2005) Molecular interactions between matrilysin and the matrix metalloproteinase inhibitor doxycycline investigated by deuterium exchange mass spectrometry. Mol Pharmacol 67:1128–36PubMedCrossRefGoogle Scholar
  30. 30.
    Fishbein MC, Maclean D, Maroko PR (1978) Experimental myocardial infarction in the rat: qualitative and quantitative changes during pathologic evolution. Am J Pathol 90:57–70PubMedGoogle Scholar
  31. 31.
    Villarreal F, Omens J, Dillmann W, Risteli J, Nguyen J, Covell J (2004) Early degradation and serum appearance of type I collagen fragments after myocardial infarction. J Mol Cell Cardiol 36:597–601PubMedCrossRefGoogle Scholar
  32. 32.
    Garcia RA, Brown KL, Pavelec RS, Go KV, Covell JW, Villarreal FJ (2005) Abnormal cardiac wall motion and early matrix metalloproteinase activity. Am J Physiol Heart Circ Physiol 288:H1080–7PubMedCrossRefGoogle Scholar
  33. 33.
    Vivaldi MT, Eyre DR, Kloner RA, Schoen FJ (1987) Effects of methylprednisolone on collagen biosynthesis in healing acute myocardial infarction. Am J Cardiol 60:424–5PubMedCrossRefGoogle Scholar
  34. 34.
    Hammerman H, Kloner RA, Hale S, Schoen FJ, Braunwald E (1983) Dose-dependent effects of short-term methylprednisolone on myocardial infarct extent, scar formation, and ventricular function. Circulation 68:446–52PubMedGoogle Scholar
  35. 35.
    Hammerman H, Kloner RA, Schoen FJ, Brown EJ Jr, Hale S, Braunwald E (1983) Indomethacin-induced scar thinning after experimental myocardial infarction. Circulation 67:1290–5PubMedGoogle Scholar
  36. 36.
    Brown EJ Jr, Kloner RA, Schoen FJ, Hammerman H, Hale S, Braunwald E (1983) Scar thinning due to ibuprofen administration after experimental myocardial infarction. Am J Cardiol 51:877–83PubMedCrossRefGoogle Scholar
  37. 37.
    Hammerman H, Kloner RA, Schoen FJ, Brown EJ Jr, Hale SL, Braunwald E (1982) The effects of early indomethacin administration on late scar formation following myocardial infarction. Trans Assoc Am Physicians 95:104–9PubMedGoogle Scholar
  38. 38.
    Lichey J, Charissis G, Braunsdorf M, Franke J, Hahn W (1979) Accumulation of 99mTc-tetracycline in lung infarction area. An experimental study. Respiration 37:220–3PubMedCrossRefGoogle Scholar
  39. 39.
    Ryan CF, Athari-Nejad A, Holcslaw TL (1979) Quantitation of isoproterenol-induced myocardial necrosis with 3H-tetracycline. Res Commun Chem Pathol Pharmacol 25:489–501PubMedGoogle Scholar
  40. 40.
    Modrak JB, Rovang KS (1981) Estimation of infarct size by determination of myocardial 3H-tetracycline accumulation in the coronary ligated rat. Res Commun Chem Pathol Pharmacol 34:149–52PubMedGoogle Scholar
  41. 41.
    Griffin MO, Jinno M, Miles LA, Villarreal FJ (2005) Reduction of myocardial infarct size by doxycycline: a role for plasmin inhibition. Mol Cell Biochem 270:1–11PubMedCrossRefGoogle Scholar
  42. 42.
    Daugherty A, Dunn JL, Rateri DL, Heinecke JW (1994) Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J Clin Invest 94:437–44PubMedCrossRefGoogle Scholar
  43. 43.
    Jackson RT, Waitzman MB (1967) The long-term effects of a single dose of methyl prednisolone on 35S uptake in ocular and nasal tissue. Biochem Pharmacol 16:1115–7PubMedCrossRefGoogle Scholar
  44. 44.
    Franklin IJ, Harley SL, Greenhalgh RM, Powell JT (1999) Uptake of tetracycline by aortic aneurysm wall and its effect on inflammation and proteolysis. Br J Surg 86:771–5PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Ricardo A. Garcia
    • 1
  • Katrina V. Go
    • 1
  • Francisco J. Villarreal
    • 1
    • 2
  1. 1.Department of MedicineUniversity of California San DiegoLa JollaUSA
  2. 2.CardiologyUCSDLa JollaUSA

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