| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
From the Department of Laboratory Medicine and Pathobiology and theDepartment of Medicine,*
University of Toronto, Toronto; and theTerrence Donnelly Cardiovascular ResearchLaboratories,
St. Michael’s Hospital,Toronto, Ontario, Canada
The tetracyclines function as antibiotics by inhibiting bacterial protein synthesis, but recent work has shown that they are pluripotent drugs that affect many mammalian cell functions including proliferation, migration, apoptosis, and matrix remodeling. Because all of these processes have been implicated in arterial intimal lesion development, the objective of these studies was to examine the effect of doxycycline treatment using a well-characterized model of neointimal thickening, balloon catheter denudation of the rat carotid artery. Rats were treated with 30-mg/kg/day doxycycline. Doxycycline reduced the activity of matrix metalloproteinase (MMP)-2 and MMP-9 in the arterial wall, and inhibited smooth muscle cell migration from media to intima by 77% at 4 days after balloon injury. Replication of smooth muscle cells in the intima at 7 days was reduced from 28.3 ± 2.5% in controls to 17.0 ± 2.8% in doxycycline-treated rats. The synthesis of elastin and collagen was not affected, but accumulation of elastin was blocked in the doxycycline-treated rats. By contrast, collagen accumulation was not affected, which led to the formation of a more collagen-rich intima. At 28 days after injury, the intimal:medial ratio was significantly reduced from 1.67 ± 0.09 in control rats to 1.36 ± 0.06 in the doxycycline-treated rats. This study shows that doxycycline is an effective inhibitor of cell proliferation, migration, and MMP activity in vivo. Further study in more complicated models of atherosclerosis and restenosis iswarranted.
This article has been cited by other articles:
 |
|
 |
|
  N. El-Bizri, C. Guignabert, L. Wang, A. Cheng, K. Stankunas, C.-P. Chang, Y. Mishina, and M. Rabinovitch SM22{alpha}-targeted deletion of bone morphogenetic protein receptor 1A in mice impairs cardiac and vascular development, and influences organogenesis Development, September 1, 2008; 135(17): 2981 - 2991. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Ho, G. Hou, J. G. Pickering, G. Hannigan, B. L. Langille, and M. P. Bendeck Integrin-Linked Kinase in the Vascular Smooth Muscle Cell Response to Injury Am. J. Pathol., July 1, 2008; 173(1): 278 - 288. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Dufourcq, L. Leroux, J. Ezan, B. Descamps, J.-M. D. Lamaziere, P. Costet, C. Basoni, C. Moreau, U. Deutsch, T. Couffinhal, et al. Regulation of Endothelial Cell Cytoskeletal Reorganization by a Secreted Frizzled-Related Protein-1 and Frizzled 4- and Frizzled 7-Dependent Pathway: Role in Neovessel Formation Am. J. Pathol., January 1, 2008; 172(1): 37 - 49. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Z. Lee, Z. Xue, Y. Zhu, G.-Y. Yang, and W. L. Young Matrix Metalloproteinase-9 Inhibition Attenuates Vascular Endothelial Growth Factor-Induced Intracerebral Hemorrhage Stroke, September 1, 2007; 38(9): 2563 - 2568. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Johnson, R. Fritsche-Danielson, M. Behrendt, A. Westin-Eriksson, H. Wennbo, M. Herslof, M. Elebring, S. J. George, W. L. McPheat, and C. L. Jackson Effect of broad-spectrum matrix metalloproteinase inhibition on atherosclerotic plaque stability Cardiovasc Res, August 1, 2006; 71(3): 586 - 595. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Qin, M. A. Corriere, L. M. Matrisian, and R. J. Guzman Matrix Metalloproteinase Inhibition Attenuates Aortic Calcification Arterioscler. Thromb. Vasc. Biol., July 1, 2006; 26(7): 1510 - 1516. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Franco, B. Ho, D. Mulholland, G. Hou, M. Islam, K. Donaldson, and M. P. Bendeck Doxycycline Alters Vascular Smooth Muscle Cell Adhesion, Migration, and Reorganization of Fibrillar Collagen Matrices Am. J. Pathol., May 1, 2006; 168(5): 1697 - 1709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P.G. Sluijter, D. P.V. de Kleijn, and G. Pasterkamp Vascular remodeling and protease inhibition-bench to bedside Cardiovasc Res, February 15, 2006; 69(3): 595 - 603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Newby Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates Cardiovasc Res, February 15, 2006; 69(3): 614 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Cardoso and M. J. Saraiva Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model FASEB J, February 1, 2006; 20(2): 234 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. de Nooijer, C.J.N. Verkleij, J.H. von der Thusen, J.W. Jukema, E.E. van der Wall, Th. J.C. van Berkel, A.H. Baker, and E.A.L. Biessen Lesional Overexpression of Matrix Metalloproteinase-9 Promotes Intraplaque Hemorrhage in Advanced Lesions But Not at Earlier Stages of Atherogenesis Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 340 - 346. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C.T. Palei, R. A.G. Zaneti, G. M. Fortuna, R. F. Gerlach, and J. E. Tanus-Santos Hemodynamic Benefits of Matrix Metalloproteinase-9 Inhibition by Doxycycline During Experimental Acute Pulmonary Embolism Angiology, September 1, 2005; 56(5): 611 - 617. [Abstract] [PDF]
|
|
|
|
 |
|
 C. Bouvet, L.-A. Gilbert, D. Girardot, D. deBlois, and P. Moreau Different Involvement of Extracellular Matrix Components in Small and Large Arteries During Chronic NO Synthase Inhibition Hypertension, March 1, 2005; 45(3): 432 - 437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Newby Dual Role of Matrix Metalloproteinases (Matrixins) in Intimal Thickening and Atherosclerotic Plaque Rupture Physiol Rev, January 1, 2005; 85(1): 1 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Yao, Y. Chen, W. Zhai, K. Xu, W. L. Young, and G.-Y. Yang Minocycline Exerts Multiple Inhibitory Effects on Vascular Endothelial Growth Factor-Induced Smooth Muscle Cell Migration: The Role of ERK1/2, PI3K, and Matrix Metalloproteinases Circ. Res., August 20, 2004; 95(4): 364 - 371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Z. Lee, B. Xu, T. Hashimoto, C. E. McCulloch, G.-Y. Yang, and W. L. Young Doxycycline Suppresses Cerebral Matrix Metalloproteinase-9 and Angiogenesis Induced by Focal Hyperstimulation of Vascular Endothelial Growth Factor in a Mouse Model Stroke, July 1, 2004; 35(7): 1715 - 1719. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Pyo, K. K. Jensen, M. T. Wiekowski, D. Manfra, A. Alcami, M. B. Taubman, and S. A. Lira Inhibition of Intimal Hyperplasia in Transgenic Mice Conditionally Expressing the Chemokine-Binding Protein M3 Am. J. Pathol., June 1, 2004; 164(6): 2289 - 2297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Brown, K. K. Desai, B. A. Vakili, C. Nouneh, H.-M. Lee, and L. M. Golub 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., April 1, 2004; 24(4): 733 - 738. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. I. Willis, D. Pierre-Paul, B. E. Sumpio, and V. Gahtan Vascular Smooth Muscle Cell Migration: Current Research and Clinical Implications Vascular and Endovascular Surgery, January 1, 2004; 38(1): 11 - 23. [Abstract] [PDF]
|
|
|
|
|
|
C. Whatling, W. McPheat, and E. Hurt-Camejo Matrix Management: Assigning Different Roles for MMP-2 and MMP-9 in Vascular Remodeling Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 10 - 11. [Full Text] [PDF]
|
|
|
|
|
|
C. Johnson and Z. S. Galis Matrix Metalloproteinase-2 and -9 Differentially Regulate Smooth Muscle Cell Migration and Cell-Mediated Collagen Organization Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 54 - 60. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Islam, C. D. Franco, D. W. Courtman, and M. P. Bendeck A Nonantibiotic Chemically Modified Tetracycline (CMT-3) Inhibits Intimal Thickening Am. J. Pathol., October 1, 2003; 163(4): 1557 - 1566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Teshima, N. Hayashida, H. Yano, M. Nishimi, E. Tayama, S. Fukunaga, H. Akashi, T. Kawara, and S. Aoyagi Obstruction of St Jude medical valves in the aortic position: histology and immunohistochemistry of pannus J. Thorac. Cardiovasc. Surg., August 1, 2003; 126(2): 401 - 407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. CARDOSO, G. MERLINI, and M. J. SARAIVA 4'-iodo-4'-Deoxydoxorubicin and tetracyclines disrupt transthyretin amyloid fibrils in vitro producing noncytotoxic species: screening for TTR fibril disrupters FASEB J, May 1, 2003; 17(8): 803 - 809. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Asanuma, R. Magid, C. Johnson, R. M. Nerem, and Z. S. Galis Uniaxial strain upregulates matrix-degrading enzymes produced by human vascular smooth muscle cells Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1778 - H1784. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Wang, S.-H. Li, R. D. Weisel, P. W.M. Fedak, A. S. Dumont, P. Szmitko, R.-K. Li, D. A.G. Mickle, and S. Verma C-Reactive Protein Upregulates Angiotensin Type 1 Receptors in Vascular Smooth Muscle Circulation, April 8, 2003; 107(13): 1783 - 1790. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. W. M. Fedak, S. M. Altamentova, R. D. Weisel, N. Nili, N. Ohno, S. Verma, T.-Y. J. Lee, C. Kiani, D. A. G. Mickle, B. H. Strauss, et al. Matrix remodeling in experimental and human heart failure: a possible regulatory role for TIMP-3 Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H626 - H634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Bucciarelli, T. Wendt, W. Qu, Y. Lu, E. Lalla, L. L. Rong, M. T. Goova, B. Moser, T. Kislinger, D. C. Lee, et al. RAGE Blockade Stabilizes Established Atherosclerosis in Diabetic Apolipoprotein E-Null Mice Circulation, November 26, 2002; 106(22): 2827 - 2835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.L.M. Lamfers, J.M. Grimbergen, M.C. Aalders, M.J. Havenga, M.R. de Vries, L.G.M. Huisman, V.W.M. van Hinsbergh, and P.H.A. Quax Gene Transfer of the Urokinase-Type Plasminogen Activator Receptor-Targeted Matrix Metalloproteinase Inhibitor TIMP-1.ATF Suppresses Neointima Formation More Efficiently Than Tissue Inhibitor of Metalloproteinase-1 Circ. Res., November 15, 2002; 91(10): 945 - 952. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Cho and M. A. Reidy Matrix Metalloproteinase-9 Is Necessary for the Regulation of Smooth Muscle Cell Replication and Migration After Arterial Injury Circ. Res., November 1, 2002; 91(9): 845 - 851. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. S. Galis, C. Johnson, D. Godin, R. Magid, J. M. Shipley, R. M. Senior, and E. Ivan Targeted Disruption of the Matrix Metalloproteinase-9 Gene Impairs Smooth Muscle Cell Migration and Geometrical Arterial Remodeling Circ. Res., November 1, 2002; 91(9): 852 - 859. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Bendeck Matrix Metalloproteinases: Are They Antiatherogenic but Proaneurysmal? Circ. Res., May 3, 2002; 90(8): 836 - 837. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
