MMP inhibition in abdominal aortic aneurysms. Rationale for a prospective randomized clinical trial.
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 metallo-proteinases (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.
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA. thompsonr@msnotes.wustl.edu
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D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001012:Aorta, Abdominal / Q000201:enzymology / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000503:physiopathology / Q000601:surgery; D017364:Collagenases / Q000235:genetics; D003238:Connective Tissue / Q000187:drug effects / Q000473:pathology; D004318:Doxycycline / Q000627:therapeutic use*; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology; D011480:Protease Inhibitors / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic
D000900:Anti-Bacterial Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline