This Article Full Text Full Text (PDF) All Versions of this Article: 33/12/2858    most recent 01.STR.0000038098.04291.F6v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Axisa, B. Articles by Napoli, C. Search for Related Content PubMed PubMed Citation Articles by Axisa, B. Articles by Napoli, C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Carotid Artery Disease Hazardous Substances DB DOXYCYCLINE Related Collections Cell biology/structural biology Carotid Stenosis Other Stroke Treatment - Medical Carotid endarterectomy Mechanism of atherosclerosis/growth factors

(Stroke. 2002;33:2858.)
© 2002 American Heart Association, Inc.

Original Contributions

Prospective, Randomized, Double-Blind Trial Investigating the Effect of Doxycycline on Matrix Metalloproteinase Expression Within Atherosclerotic Carotid Plaques

Benedict Axisa, FRCS; Ian M. Loftus, MD, FRCS; A. Ross Naylor, MD, FRCS; Steven Goodall, BSc; Louise Jones, PhD, FRCPath; Peter R.F. Bell, MD, FRCS Matthew M. Thompson, MD, FRCS

From the Departments of Surgery and Pathology (L.J.), University of Leicester, Leicester, UK.

Correspondence to Professor M.M. Thompson, Professor of Vascular Surgery, Department of Vascular Surgery, 4th Floor St James Wing, St George’s Hospital, Blackshaw Rd, London SW17 0QT, UK. E-mail mattT11{at}aol.com

Background and Purpose— Elevated levels of matrix metalloproteinases (MMPs), particularly MMP-1 and MMP-9, have been implicated in plaque rupture. It has been suggested that inhibition of MMPs may stabilize vulnerable atherosclerotic plaques and improve clinical outcome. The aim of the study was to investigate the ability of doxycycline, a nonspecific MMP inhibitor, to reduce MMP concentration in carotid atheroma.

Methods— The study design was a prospective, double-blind randomized trial. One hundred patients requiring carotid endarterectomy were randomized to receive 200 mg/d doxycycline or placebo for 2 to 8 weeks before surgery. During endarterectomy, carotid plaques were retrieved. The concentrations of MMPs and doxycycline were determined in the atherosclerotic tissue by enzyme-linked immunosorbent assay and high-performance liquid chromatography, respectively. Clinical events were recorded, as was the rate of preoperative embolization (transcranial Doppler).

Results— Analysis of endarterectomized specimens demonstrated a mean doxycycline concentration of 6.0 µg/g wet weight in treated patients. Administration of doxycycline significantly reduced the concentration of MMP-1 in carotid plaques from a mean of 14.8 to 10.3 ng/100g wet weight (P=0.038). This difference was due to decreased MMP-1 transcript (P<0.001). There was no difference in any other MMP (MMP-2, -3, or -9) or tissue inhibitor of matrix metalloproteinases–1 or –2.

Conclusions— Doxycycline penetrated atherosclerotic plaques with acceptable tissue levels. This resulted in a reduction in MMP-1 concentration because of decreased expression.

Editorial Comment

Claudio Napoli, MD, PhD, Guest Editor

This article has been cited by other articles:

				Y.-C. Cheng, W.-H. L. Kao, B. D. Mitchell, J. R. O'Connell, H. Shen, P. F. McArdle, Q. Gibson, K. A. Ryan, A. R. Shuldiner, and T. I. Pollin Genome-Wide Association Scan Identifies Variants near Matrix Metalloproteinase (MMP) Genes on Chromosome 11q21-22 Strongly Associated With Serum MMP-1 Levels Circ Cardiovasc Genet, August 1, 2009; 2(4): 329 - 337. [Abstract] [Full Text] [PDF]

				P. Akkaya, G. Onalan, N. Haberal, N. Bayraktar, B. Mulayim, and H. B. Zeyneloglu Doxycycline causes regression of endometriotic implants: a rat model Hum. Reprod., August 1, 2009; 24(8): 1900 - 1908. [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]

				G. Stoll and M. Bendszus Inflammation and Atherosclerosis: Novel Insights Into Plaque Formation and Destabilization Stroke, July 1, 2006; 37(7): 1923 - 1932. [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]

				C. M. Dollery and P. Libby Atherosclerosis and proteinase activation Cardiovasc Res, February 15, 2006; 69(3): 625 - 635. [Abstract] [Full Text] [PDF]

				B. Galobardes, G. D. Smith, M. Jeffreys, S. Kinra, and P. McCarron Acne in Adolescence and Cause-specific Mortality: Lower Coronary Heart Disease but Higher Prostate Cancer Mortality: The Glasgow Alumni Cohort Study Am. J. Epidemiol., June 15, 2005; 161(12): 1094 - 1101. [Abstract] [Full Text] [PDF]

				K.J. Molloy, M.M. Thompson, J.L. Jones, E.C. Schwalbe, P.R.F. Bell, A.R. Naylor, and I.M. Loftus Unstable Carotid Plaques Exhibit Raised Matrix Metalloproteinase-8 Activity Circulation, July 20, 2004; 110(3): 337 - 343. [Abstract] [Full Text] [PDF]

				A. R. Morgan, K. Rerkasem, P. J. Gallagher, B. Zhang, G. E. Morris, P. C. Calder, R. F. Grimble, P. Eriksson, W. L. McPheat, C. P. Shearman, et al. Differences in Matrix Metalloproteinase-1 and Matrix Metalloproteinase-12 Transcript Levels Among Carotid Atherosclerotic Plaques With Different Histopathological Characteristics Stroke, June 1, 2004; 35(6): 1310 - 1315. [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]

				L. Hao, M. Du, A. Lopez-Campistrous, and C. Fernandez-Patron Agonist-Induced Activation of Matrix Metalloproteinase-7 Promotes Vasoconstriction Through the Epidermal Growth Factor-Receptor Pathway Circ. Res., January 9, 2004; 94(1): 68 - 76. [Abstract] [Full Text] [PDF]

				S. V. Vadlamuri, J. Media, S. S. Sankey, A. Nakeff, G. Divine, and S. A. Rempel SPARC affects glioma cell growth differently when grown on brain ECM proteins in vitro under standard versus reduced-serum stress conditions Neuro-oncol, October 1, 2003; 5(4): 244 - 254. [Abstract] [PDF]

				P. Stenvinkel, R. Pecoits-Filho, and B. Lindholm Coronary Artery Disease in End-Stage Renal Disease: No Longer a Simple Plumbing Problem J. Am. Soc. Nephrol., July 1, 2003; 14(7): 1927 - 1939. [Full Text] [PDF]

				B. Axisa, I. M. Loftus, A. R. Naylor, S. Goodall, L. Jones, P. R.F. Bell, M. M. Thompson, and C. Napoli Prospective, Randomized, Double-Blind Trial Investigating the Effect of Doxycycline on Matrix Metalloproteinase Expression Within Atherosclerotic Carotid Plaques * Editorial Comment Stroke, December 1, 2002; 33(12): 2858 - 2864. [Abstract] [Full Text] [PDF]