Matrix metalloproteinases as drug targets in acute pulmonary embolism

Current Drug Targets

Volumn 14, Issue 3, 2013, Pages 344-352

  Neto Neves, Evandro M ^a   Kiss, Tamás ^b   Mühl, Diána ^b   Tanus Santos, Jose E ^a  

^a UNIVERSITY OF SÃO PAULO   (Brazil)

^b UNIVERSITY OF PÉCS   (Hungary)

Author keywords

Acute pulmonary thromboembolism; Matrix metalloproteinases; Pulmonary circulation; Pulmonary embolism; Pulmonary hypertension; Therapy

Indexed keywords

ALTEPLASE; BRAIN NATRIURETIC PEPTIDE; D DIMER; DOXYCYCLINE; ENDOTHELIN 1; FATTY ACID BINDING PROTEIN; GELATINASE A; GELATINASE B; KETOROLAC; MATRIX METALLOPROTEINASE; MINOCYCLINE; MYOSIN LIGHT CHAIN; NITRIC OXIDE; OXYGEN RADICAL; PROSTACYCLIN; REACTIVE OXYGEN METABOLITE; SCLEROPROTEIN; SEROTONIN; STAT PROTEIN; TETRACYCLINE DERIVATIVE; THROMBOXANE A2; TISSUE INHIBITOR OF METALLOPROTEINASE; TROPONIN I; VASOACTIVE AGENT;

ACUTE HEART INFARCTION; BLEEDING; BLOOD CLOT LYSIS; BRAIN HEMORRHAGE; CELL DAMAGE; CELL MIGRATION; COR PULMONALE; DRUG TARGETING; HEART MUSCLE INJURY; HEART MUSCLE ISCHEMIA; HEART RIGHT VENTRICLE PRESSURE; HEMODYNAMICS; HUMAN; HYPOXEMIA; LUNG EMBOLISM; LUNG INJURY; MORBIDITY; MORTALITY; NONHUMAN; PATHOPHYSIOLOGY; PREDICTIVE VALUE; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PULMONARY HYPERTENSION; REVIEW; RISK FACTOR; UPREGULATION;

EID: 84876734919     PISSN: 13894501     EISSN: 18735592     Source Type: Journal    
DOI: 10.2174/138945013804998954     Document Type: Review

References (106)

1. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999; 353: 1386-9.
2. Stein PD, Kayali F, Olson RE. Estimated case fatality rate of pulmonary embolism, 1979 to 1998. Am J Cardiol 2004; 93: 1197-9.
3. Karwinski B, Svendsen E. Comparison of clinical and postmortem diagnosis of pulmonary embolism. J Clin Pathol 1989; 42: 135-9.
4. Goldhaber SZ. Pulmonary embolism. N Engl J Med 1998; 339: 93-104.
5. Meneveau N, Ming LP, Seronde MF, et al. In-hospital and longterm outcome after sub-massive and massive pulmonary embolism submitted to thrombolytic therapy. Eur Heart J 2003; 24: 1447-54.
6. Stratmann G, Gregory GA. Neurogenic and humoral vasoconstriction in acute pulmonary thromboembolism. Anesth Analg 2003; 97: 341-54.
7. Jardin F, Vieillard-Baron A. Acute cor pulmonale. Curr Opin Crit Care 2009; 15: 67-70.
8. Galie N, Torbicki A, Barst R, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 2004; 25: 2243-78.
9. Muhl D, Furedi R, Cristofari J, et al. Evaluation of oxidative stress in the thrombolysis of pulmonary embolism. J Thromb Thrombolysis 2006; 22: 221-8.
10. Albelda SM, Smith CW, Ward PA. Adhesion molecules and inflammatory injury. FASEB J 1994; 8: 504-12.
11. Wagner JG, Roth RA. Neutrophil migration mechanisms, with an emphasis on the pulmonary vasculature. Pharmacol Rev 2000; 52: 349-74.
12. Herve P, Launay JM, Scrobohaci ML, et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 1995; 99: 249-54.
13. Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991; 114: 464-9.
14. 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.
15. Wang W, Sawicki G, Schulz R. Peroxynitrite-induced myocardial injury is mediated through matrix metalloproteinase-2. Cardiovasc Res 2002; 53: 165-74.
16. Jeffery TK, Morrell NW. Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension. Prog Cardiovasc Dis 2002; 45: 173-202.
17. Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev 2007; 87: 1285-342.
18. 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.
19. Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 2002; 90: 251-62.
20. Castro MM, Rizzi E, Prado CM, Rossi MA, Tanus-Santos JE, Gerlach RF. Imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases in hypertensive vascular remodeling. Matrix Biol 2010; 29: 194-201.
21. 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.
22. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006; 69: 562-73.
23. Nagase H, Woessner JF, Jr. Matrix metalloproteinases. J Biol Chem 1999; 274: 21491-4.
24. Hadler-Olsen E, Fadnes B, Sylte I, Uhlin-Hansen L, Winberg JO. Regulation of matrix metalloproteinase activity in health and disease. Febs J 2011; 278: 28-45.
25. Marson BP, Lacchini R, Belo V, et al. Matrix metalloproteinase (MMP)-2 genetic variants modify the circulating MMP-2 levels in end-stage kidney disease. Am J Nephrol 2012; 35: 209-15.
26. Marson BP, Lacchini R, Belo V, et al. Functional matrix metalloproteinase (MMP)-9 genetic variants modify the effects of hemodialysis on circulating MMP-9 levels. Clin Chim Acta 2012; 414C: 46-51.
27. Fontana V, Silva PS, Belo VA, et al. Consistent alterations of circulating matrix metalloproteinases levels in untreated hypertensives and in spontaneously hypertensive rats: a relevant pharmacological target. Basic Clin Pharmacol Toxicol 2012; 109: 130-7.
28. Fontana V, Silva PS, Gerlach RF, Tanus-Santos JE. Circulating matrix metalloproteinases and their inhibitors in hypertension. Clin Chim Acta 2012; 413: 656-62.
29. Castro MM, Kandasamy AD, Youssef N, Schulz R. Matrix metalloproteinase inhibitor properties of tetracyclines: therapeutic potential in cardiovascular diseases. Pharmacol Res 2011; 64: 551-60.
30. Kandasamy AD, Chow AK, Ali MA, Schulz R. Matrix metalloproteinase-2 and myocardial oxidative stress injury: beyond the matrix. Cardiovasc Res 2009; 85: 413-23.
31. Van Wart HE, Birkedal-Hansen H. 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 1990; 87: 5578-82.
32. Okamoto T, Akaike T, Sawa T, Miyamoto Y, van der Vliet A, Maeda H. Activation of matrix metalloproteinases by peroxynitriteinduced protein S-glutathiolation via disulfide S-oxide formation. J Biol Chem 2001; 276: 29596-602.
33. Viappiani S, Nicolescu AC, Holt A, et al. Activation and modulation of 72kDa matrix metalloproteinase-2 by peroxynitrite and glutathione. Biochem Pharmacol 2009; 77: 826-34.
34. Schulz R. Intracellular targets of matrix metalloproteinase-2 in cardiac disease: rationale and therapeutic approaches. Annu Rev Pharmacol Toxicol 2007; 47: 211-42.
35. Dias-Junior CA, Cau SB, Oliveira AM, et al. Nitrite or sildenafil, but not BAY 41-2272, blunt acute pulmonary embolism-induced increases in circulating matrix metalloproteinase-9 and oxidative stress. Thromb Res 2009; 124: 349-55.
36. Dias-Junior CA, Souza-Costa DC, Zerbini T, da Rocha JB, Gerlach RF, Tanus-Santos JE. The effect of sildenafil on pulmonary embolism-induced oxidative stress and pulmonary hypertension. Anesth Analg 2005; 101: 115-20.
37. Souza-Costa DC, Zerbini T, Metzger IF, Rocha JB, Gerlach RF, Tanus-Santos JE. l-Arginine attenuates acute pulmonary embolisminduced oxidative stress and pulmonary hypertension. Nitric Oxide 2005; 12: 9-14.
38. 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.
39. Alfonso-Jaume MA, Bergman MR, Mahimkar R, et al. Cardiac ischemia-reperfusion injury induces matrix metalloproteinase-2 expression through the AP-1 components FosB and JunB. Am J Physiol Heart Circ Physiol 2006; 291: H1838-46.
40. Deschamps AM, Spinale FG. Pathways of matrix metalloproteinase induction in heart failure: bioactive molecules and transcriptional regulation. Cardiovasc Res 2006; 69: 666-76.
41. Cau SB, Guimaraes DA, Rizzi E, et al. Pyrrolidine dithiocarbamate down-regulates vascular matrix metalloproteinases and ameliorates vascular dysfunction and remodelling in renovascular hypertension. Br J Pharmacol 2011; 164: 372-81.
42. Belo VA, Souza-Costa DC, Luizon MR, et al. Matrix metalloproteinase-9 genetic variations affect MMP-9 levels in obese children. Int J Obes (Lond) 2012; 36: 69-75.
43. Goncalves FM, Martins-Oliveira A, Lacchini R, et al. Matrix metalloproteinase (MMP)-2 gene polymorphisms affect circulating MMP-2 levels in patients with migraine with aura. Gene 2013; 512:35-40.
44. Lacchini R, Jacob-Ferreira AL, Luizon MR, et al. Matrix metalloproteinase 9 gene haplotypes affect left ventricular hypertrophy in hypertensive patients. Clin Chim Acta 2010; 411:1940-4.
45. Lacchini R, Jacob-Ferreira AL, Luizon MR, et al. Common matrix metalloproteinase 2 gene haplotypes may modulate left ventricular remodelling in hypertensive patients. J Hum Hypertens 2012; 26: 171-7.
46. 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.
47. 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.
48. 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.
49. Eagleton MJ, Henke PK, Luke CE, et al. Inflammation and intimal hyperplasia associated with experimental pulmonary embolism. J Vasc Surg 2002; 36: 581-8.
50. Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA, Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9). Crit Rev Biochem Mol Biol 2002; 37: 375-536.
51. Neto-Neves EM, Dias-Junior CA, Uzuelli JA, et al. Sildenafil improves the beneficial hemodynamic effects exerted by atorvastatin during acute pulmonary thromboembolism. Eur J Pharmacol 2011; 670: 554-60.
52. Dias-Junior CA, Neto-Neves EM, Montenegro MF, Tanus-Santos JE. Hemodynamic effects of inducible nitric oxide synthase inhibition combined with sildenafil during acute pulmonary embolism. Nitric Oxide 2010; 23: 284-8.
53. Dias-Junior CA, Sertorio JT, Tanus-Santos JE. Aminoguanidine produces beneficial haemodynamic effects in a canine model of acute pulmonary thromboembolism. Acta Physiol (Oxf) 2007; 191: 189-96.
54. Dias-Junior CA, Tanus-Santos JE. Hemodynamic effects of sildenafil interaction with a nitric oxide donor compound in a dog model of acute pulmonary embolism. Life Sci 2006; 79: 469-74.
55. 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.
56. 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.
57. Tanus-Santos JE, Gordo WM, Udelsmann A, Cittadino MH, Moreno H, Jr. Nonselective endothelin-receptor antagonism attenuates hemodynamic changes after massive pulmonary air embolism in dogs. Chest 2000; 118: 175-9.
58. Tanus-Santos JE, Gordo WM, Udelsmann A, Moreno H, Jr. The hemodynamic effects of endothelin receptor antagonism during a venous air infusion in dogs. Anesth Analg 2000; 90: 102-6.
59. Fernandez-Patron C, Stewart KG, Zhang Y, Koivunen E, Radomski MW, Davidge ST. Vascular matrix metalloproteinase-2-dependent cleavage of calcitonin gene-related peptide promotes vasoconstriction. Circ Res 2000; 87: 670-6.
60. Barnes PJ, Liu SF. Regulation of pulmonary vascular tone. Pharmacol Rev 1995; 47: 87-131.
61. Martinez A, Oh HR, Unsworth EJ, et al. Matrix metalloproteinase-2 cleavage of adrenomedullin produces a vasoconstrictor out of a vasodilator. Biochem J 2004; 383: 413-8.
62. Eagleton MJ, Henke PK, Luke CE, et al. Southern Association for Vascular Surgery William J. von Leibig Award. Inflammation and intimal hyperplasia associated with experimental pulmonary embolism. J Vasc Surg 2002; 36: 581-8.
63. Montaner J, Alvarez-Sabin J, Molina CA, et al. Matrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke. Stroke 2001; 32: 2762-7.
64. Rosell A, Cuadrado E, Ortega-Aznar A, Hernandez-Guillamon M, Lo EH, Montaner J. MMP-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke 2008; 39: 1121-6.
65. Cuadrado E, Ortega L, Hernandez-Guillamon M, et al. Tissue plasminogen activator (t-PA) promotes neutrophil degranulation and MMP-9 release. J Leukoc Biol 2008; 84: 207-14.
66. Muhl D, Ghosh S, Uzuelli JA, Lantos J, Tanus-Santos JE. Increases in circulating matrix metalloproteinase-9 levels following fibrinolysis for acute pulmonary embolism. Thromb Res 2010; 125: 549-53.
67. Arcasoy SM, Kreit JW. Thrombolytic therapy of pulmonary embolism: a comprehensive review of current evidence. Chest 1999; 115: 1695-707.
68. Ning M, Furie KL, Koroshetz WJ, et al. Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke. Neurology 2006; 66: 1550-5.
69. Machado LS, Sazonova IY, Kozak A, et al. Minocycline and tissue-type plasminogen activator for stroke: assessment of interaction potential. Stroke 2009; 40: 3028-33.
70. Sumii T, Lo EH. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke 2002; 33: 831-6.
71. Murata Y, Rosell A, Scannevin RH, Rhodes KJ, Wang X, Lo EH. Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke 2008; 39: 3372-7.
72. Chelladurai P, Seeger W, Pullamsetti SS. Matrix metalloproteinases and their inhibitors in pulmonary hypertension. Eur Respir J 2012; 40: 766-82.
73. Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest 2002; 121: 877-905.
74. 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.
75. Schulz R. Intracellular targets of matrix metalloproteinase-2 in cardiac disease: rationale and therapeutic approaches. Annu Rev Pharmacol Toxicol 2007; 47: 211-42.
76. Ali MA, Cho WJ, Hudson B, Kassiri Z, Granzier H, Schulz R. Titin is a target of matrix metalloproteinase-2: implications in myocardial ischemia/reperfusion injury. Circulation 2010; 122: 2039-47.
77. Cheung PY, Sawicki G, Wozniak M, Wang W, Radomski MW, Schulz R. Matrix metalloproteinase-2 contributes to ischemiareperfusion injury in the heart. Circulation 2000; 101: 1833-9.
78. Kandasamy AD, Chow AK, Ali MA, Schulz R. Matrix metalloproteinase-2 and myocardial oxidative stress injury: beyond the matrix. Cardiovasc Res 2010; 85: 413-23.
79. Lalu MM, Pasini E, Schulze CJ, et al. Ischaemia-reperfusion injury activates matrix metalloproteinases in the human heart. Eur Heart J 2005; 26: 27-35.
80. Sawicki G, Leon H, Sawicka J, et al. Degradation of myosin light chain in isolated rat hearts subjected to ischemia-reperfusion injury: a new intracellular target for matrix metalloproteinase-2. Circulation 2005; 112: 544-52.
81. Wang W, Schulze CJ, Suarez-Pinzon WL, Dyck JR, Sawicki G, Schulz R. Intracellular action of matrix metalloproteinase-2 accounts for acute myocardial ischemia and reperfusion injury. Circulation 2002; 106: 1543-9.
82. 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.
83. Horlander KT, Leeper KV. Troponin levels as a guide to treatment of pulmonary embolism. Curr Opin Pulm Med 2003; 9: 374-7.
84. Van Wart HE, Birkedal-Hansen H. 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 1990; 87: 5578-82.
85. Okamoto T, Akaike T, Sawa T, Miyamoto Y, van der Vliet A, Maeda H. Activation of matrix metalloproteinases by peroxynitriteinduced protein S-glutathiolation via disulfide S-oxide formation. J Biol Chem 2001; 276: 29596-602.
86. 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.
87. 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.
88. 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.
89. Watts JA, Gellar MA, Stuart LK, Obraztsova M, Kline JA. Proinflammatory events in right ventricular damage during pulmonary embolism: effects of treatment with ketorolac in rats. J Cardiovasc Pharmacol 2009; 54: 246-52.
90. Pieralli F, Olivotto I, Vanni S, et al. Usefulness of bedside testing for brain natriuretic peptide to identify right ventricular dysfunction and outcome in normotensive patients with acute pulmonary embolism. Am J Cardiol 2006; 97: 1386-90.
91. Konstantinides S. Clinical practice. Acute pulmonary embolism. N Engl J Med 2008; 359: 2804-13.
92. Konstantinides S, Geibel A, Olschewski M, et al. Importance of cardiac troponins I and T in risk stratification of patients with acute pulmonary embolism. Circulation 2002; 106: 1263-8.
93. Mehta NJ, Jani K, Khan IA. Clinical usefulness and prognostic value of elevated cardiac troponin I levels in acute pulmonary embolism. Am Heart J 2003; 145: 821-5.
94. Torbicki A, Perrier A, Konstantinides S, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008; 29: 2276-315.
95. Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation 2007; 116: 427-33.
96. Puls M, Dellas C, Lankeit M, et al. Heart-type fatty acid-binding protein permits early risk stratification of pulmonary embolism. Eur Heart J 2007; 28: 224-9.
97. Dunn KL, Wolf JP, Dorfman DM, Fitzpatrick P, Baker JL, Goldhaber SZ. Normal D-dimer levels in emergency department patients suspected of acute pulmonary embolism. J Am Coll Cardiol 2002; 40: 1475-8.
98. Dias-Junior CA, Gladwin MT, Tanus-Santos JE. Low-dose intravenous nitrite improves hemodynamics in a canine model of acute pulmonary thromboembolism. Free Radic Biol Med 2006; 41: 1764-70.
99. Dias-Junior CA, Montenegro MF, Florencio BC, Tanus-Santos JE. Sildenafil improves the beneficial haemodynamic effects of intravenous nitrite infusion during acute pulmonary embolism. Basic Clin Pharmacol Toxicol 2008; 103: 374-9.
100. Golub LM, Ramamurthy N, McNamara TF, et al. Tetracyclines inhibit tissue collagenase activity. A new mechanism in the treatment of periodontal disease. J Periodontal Res 1984; 19: 651-5.
101. Golub LM, Lee HM, Lehrer G, et al. Minocycline reduces gingival collagenolytic activity during diabetes. Preliminary observations and a proposed new mechanism of action. J Periodontal Res 1983; 18: 516-26.
102. Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, Sorsa T. Tetracyclines inhibit connective tissue breakdown by multiple nonantimicrobial mechanisms. Adv Dent Res 1998; 12: 12-26.
103. Meier CR, Derby LE, Jick SS, Vasilakis C, Jick H. Antibiotics and risk of subsequent first-time acute myocardial infarction. JAMA 1999; 281: 427-31.
104. Golub LM, Greenwald RA. Clinical applications of nonantibacterial tetracyclines. Part II. Pharmacol Res 2011; 64: 549-50.
105. Fridman R, Toth M, Pena D, Mobashery S. Activation of progelatinase B (MMP-9) by gelatinase A (MMP-2). Cancer Res 1995; 55: 2548-55.
106. Castro MM, Rizzi E, Ceron CS, Guimaraes DA, et al. Doxycycline ameliorates 2K-1C hypertension-induced vascular dysfunction in rats by attenuating oxidative stress and improving nitric oxide bioavailability. Nitric Oxide 2012; 26: 162-8.