MMP inhibition in abdominal aortic aneurysms

Rationale for a prospective randomized clinical trial

Robert W. Thompson, Bernard Timothy Baxter

Research output: Contribution to journalArticle

161 Citations (Scopus)

Abstract

Abdominal aortic aneurysms (AAAs) represent a chronic degenerative condition associated with a life-threatening risk of rupture. The evolution of AAAs is thought to involve the progressive degradation of aortic wall elastin and collagen, and increased local production of several matrix metalloproteinases (MMPs) has been implicated in this process. We have previously shown that tetracycline derivatives and other MMP inhibitors suppress aneurysm development in experimental animal models of AAA. Doxycycline also reduces the expression of MMP-2 and MMP-9 by human vascular wall cell types and by AAA tissue explants in vitro. To determine whether this strategy might have a role in the clinical management of small AAA, we examined the effect of doxycycline on aortic wall MMP expression in vivo. Patients were treated with doxycycline (100 mg p.o. bid) for 7 days prior to elective AAA repair, and aneurysm tissues were obtained at the time of surgery (n = 5). Tissues obtained from an equal number of untreated patients with AAA were used for comparison. By reverse transcription polymerase chain reaction and Southern blot analysis, MMP-2 and MMP-9 were both found to be abundantly expressed in the aneurysm wall. Preoperative treatment with doxycycline was associated with a 3-fold reduction in aortic wall expression of MMP-2 and a 4-fold reduction in MMP-9 (p < 0.05 compared to untreated AAA). These preliminary results suggest that even short-term treatment with doxycycline can suppress MMP expression within human AAA tissues. Given its pleiotropic effects as an MMP inhibitor, doxycycline may be particularly effective in suppressing aortic wall connective tissue degradation. While it remains to be determined whether MMP inhibition will have a clinically significant impact on aneurysm expansion, it is expected that this question can be resolved by a properly designed prospective randomized clinical trial.

Original languageEnglish (US)
Pages (from-to)159-178
Number of pages20
JournalAnnals of the New York Academy of Sciences
Volume878
DOIs
StatePublished - Jan 1 1999

Fingerprint

Doxycycline
Abdominal Aortic Aneurysm
Matrix Metalloproteinases
Randomized Controlled Trials
Tissue
Matrix Metalloproteinase 2
Aneurysm
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinase 9
Degradation
Elastin
Polymerase chain reaction
Transcription
Tetracycline
Surgery
Clinical Trials
Animals
Repair
Collagen
Southern Blotting

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

MMP inhibition in abdominal aortic aneurysms : Rationale for a prospective randomized clinical trial. / Thompson, Robert W.; Baxter, Bernard Timothy.

In: Annals of the New York Academy of Sciences, Vol. 878, 01.01.1999, p. 159-178.

Research output: Contribution to journalArticle

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