Suppression of experimental abdominal aortic aneurysms by systemic treatment with a hydroxamate-based matrix metalloproteinase inhibitor (RS 132908)

Background: Abdominal aortic aneurysms (AAAs) are associated with chronic i nflammation, disruption of medial elastin, and increased local production o f clastolytic matrix metalloproteinases (MMPs). The purpose of this study w as to investigate how treatment with a hydroxamate-based MMP antagonist (RS 132908) might affect. the development of experimental AAAs. Methods: Male Wistar rats underwent intraluminal perfusion of the abdominal aorta with 50 units of porcine pancreatic elastase followed by treatment f or 14 days with RS 132908 (100 mg/kg/day subcutaneously; n = 8) or with veh icle alone (n = 6). The external aortic diameter (AD) was measured in milli meters before elastase perfusion and at death, with AAA defined as an incre ase in AD (Delta AD) of at least 100%, Aortic wall elastin and collagen con centrations were measured with assays for desmosine and hydroxyproline, and fixed aortic tissues tt ere examined by light microscopy, Results: AAAs developed in all vehicle-treated rats, with a mean AD (+/- SE ) that increased from 1.60 +/- 0.03 mm before perfusion to 5.98 +/- 1.02 mm on day 14 (Delta AD = 276.4 +/- 67.7%), AAAs developed in only five of eig ht animals (62.5%) after MMP inhibition, with a mean AD that increased from 1.56 +/-; 0.05 mm to 3.59 +/- 0.34 mm (Delta AD = 128.1 +/-: 18.7%; P < .0 5, vs vehicle), The overall inhibition of aortic dilatation attributable to RS 132908 was 53.6 +/- 6.8%, Aortic wall desmosine fell by 85.4% in the ve hicle-heated rats (1210.6 +/- 87.8 pmol/sample to 176.7 +/- 33.4 pmol/sampl e; P < .05) but only by 65.6% in the animals treated with RS 312908 (416.2 +/- 120.5 pmol/sample), In contrast, hydroxyproline was not significantly a ffected by either elastase perfusion or drug treatment. Microscopic examina tion revealed the preservation of pericellular elastin and a greater degree of fibrocollagenous wall thickening after MMP inhibition, with no detectab le difference in the extent of inflammation. Conclusions: Systemic MMP inhibition suppresses aneurysmal dilatation in th e elastase-induced rodent: model of AAA. Consistent with its direct inhibit ory effect on various MMPs, RS 132908 promotes the preservation of aortic e lastin and appears to enhance a profibrotic response within the aortic wall . Hydroxamate-based MMP antagonists may therefore be useful in the developm ent of pharmacologic approaches to the suppression of AAAs.