Abstract | BACKGROUND: METHODS: Male Wistar rats underwent intraluminal perfusion of the abdominal aorta with 50 units of porcine pancreatic elastase followed by treatment for 14 days with RS 132908 (100 mg/kg/day subcutaneously; n = 8) or with vehicle alone (n = 6). The external aortic diameter (AD) was measured in millimeters before elastase perfusion and at death, with AAA defined as an increase in AD (DeltaAD) of at least 100%. Aortic wall elastin and collagen concentrations were measured with assays for desmosine and hydroxyproline, and fixed aortic tissues were 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 (DeltaAD = 276.4 +/- 67.7%). AAAs developed in only five of eight animals (62.5%) after MMP inhibition, with a mean AD that increased from 1.56 +/- 0.05 mm to 3.59 +/- 0.34 mm (DeltaAD = 128.1 +/- 18.7%; P <.05, 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 vehicle-treated rats (1210.6 +/- 87.8 pmol/sample to 176.7 +/- 33.4 pmol/sample; 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 affected by either elastase perfusion or drug treatment. Microscopic examination revealed the preservation of pericellular elastin and a greater degree of fibrocollagenous wall thickening after MMP inhibition, with no detectable difference in the extent of inflammation. CONCLUSIONS: Systemic MMP inhibition suppresses aneurysmal dilatation in the elastase-induced rodent model of AAA. Consistent with its direct inhibitory effect on various MMPs, RS 132908 promotes the preservation of aortic elastin and appears to enhance a profibrotic response within the aortic wall. Hydroxamate-based MMP antagonists may therefore be useful in the development of pharmacologic approaches to the suppression of AAAs.
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Authors | G Moore, S Liao, J A Curci, B C Starcher, R L Martin, R T Hendricks, J J Chen, R W Thompson |
Journal | Journal of vascular surgery
(J Vasc Surg)
Vol. 29
Issue 3
Pg. 522-32
(Mar 1999)
ISSN: 0741-5214 [Print] United States |
PMID | 10069917
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Hydroxamic Acids
- Pharmaceutical Vehicles
- Protease Inhibitors
- RS 132908
- Desmosine
- Collagen
- Elastin
- Pancreatic Elastase
- Metalloendopeptidases
- Hydroxyproline
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Topics |
- Animals
- Aorta, Abdominal
(chemistry, drug effects, pathology)
- Aortic Aneurysm, Abdominal
(chemically induced, prevention & control)
- Collagen
(analysis, drug effects)
- Desmosine
(analysis)
- Disease Models, Animal
- Elastin
(analysis, drug effects)
- Hydroxamic Acids
(administration & dosage, blood, therapeutic use)
- Hydroxyproline
(analysis)
- Injections, Intra-Arterial
- Injections, Subcutaneous
- Male
- Metalloendopeptidases
(antagonists & inhibitors)
- Pancreatic Elastase
(adverse effects)
- Pharmaceutical Vehicles
- Protease Inhibitors
(administration & dosage, blood, therapeutic use)
- Rats
- Rats, Wistar
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