MMP Inhibition in Abdominal Aortic Aneurysms: Rationale for a Prospective Randomized Clinical Trial

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 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.

Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms

“…Although the vast majority of these lesions are small and asymptomatic, their natural history is characterized by progressive growth and eventual rupture. Recognition that different MMPs participate in the pathobiology of AAAs has fostered the notion that these enzymes might be useful therapeutic targets in this disease, providing a novel approach to reduce the degradation of fibrillar proteins responsible for maintaining aortic wall tensile strength and potentially suppressing the rate of aneurysm expansion (39). The present study provides new experimental evidence in support of this concept and suggests that strategies targeting MMP-9 might be a particularly fruitful avenue for further investigation.…”

Loss of Matrix Metalloproteinase-9 or Matrix Metalloproteinase-12 Protects Apolipoprotein E–Deficient Mice Against Atherosclerotic Media Destruction but Differentially Affects Plaque Growth

“…30 The protective effect of MMP-9 and MMP-12 deficiency against atherosclerotic media degradation and accompanying ectasia and aortic dilatation suggests that these particular MMPs may play a central role in aneurysm formation since elastin degradation and aortic diameter expansion are hallmarks of this disease. 10 In regard to MMP-9, its involvement in aneurysm progression was additionally supported in 2 inflammatory models of AAA. 14, 15 The latter studies and our studies in concert argue for MMP-9, and possibly MMP-12, as potential targets to prevent aneurysm expansion before it reaches a critical size, leading to life-threatening ruptures.…”

“…7,8 In addition, tetracycline derivatives and synthetic MMP inhibitors suppressed experimental AAA. 9,10 We showed that urokinasetype plasminogen activator, in part by activation of MMPs, was essential for atherosclerotic media destruction. 11 However, none of these studies clarified a direct role for individual MMPs.…”

The Role of Matrix Metalloproteinase-9 in Cigarette Smoke–induced Emphysema

“…However, direct assessment of MMP-9 as a cause of cigarette smokeinduced emphysema has been lacking. Because Food and Drug Administration approved, commercially available compounds (e.g., doxycycline) can decrease MMP-9 activity at achievable systemic concentrations (39,40), we decided to evaluate MMP-9 in the mouse smoking model and human monocytes and alveolar macrophages. We now demonstrate that MMP-9 deletion in mice does not prevent either cigarette smoke-induced lung inflammation or cigarette smoke-induced airspace enlargement.…”