The matrix metalloproteinase inhibitor BB-94 limits expansion of experimental abdominal aortic aneurysms.
OBJECTIVE
Matrix metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix of the aortic wall and lead to the formation of abdominal aortic aneurysms (AAAs). MMP inhibitors are a class of drugs that were developed to inhibit the activity of these proteolytic enzymes and are currently being studied as a way to control inflammatory diseases and cancer metastases. In this project, BB-94 (also known as batimastat), a specific inhibitor of MMPs, was evaluated for its ability to control aneurysmal growth in an experimental AAA model.


METHODS
Experimental AAAs were created in a standard rat model by perfusing elastase into an isolated segment of aorta. The rats then were randomized to postoperatively undergo treatment daily with the MMP inhibitor BB-94 or the carrier control solution. Measurements of the aortic diameter were made at the time of initial surgery and at the time of death on postoperative day 7. Aortic tissue was obtained for histologic examination, elastin evaluation, and MAC 1-alpha antibody staining to evaluate the inflammatory response.


RESULTS
The rats that underwent treatment with BB-94 had significantly less aneurysmal dilatation and a 113% increase in aortic size, as compared with the control rats that had a 157% increase (P =.026). Histologic examination of the harvested aortas and grading of the elastin content showed a significantly greater elastin preservation in those rats that were treated with BB-94 as compared with the control rats (P =.036). MAC 1-alpha antibody staining showed an attenuation of the inflammatory response in the group of rats that underwent treatment with BB-94. Morphologic examination also revealed that the control of the inflammatory response correlated with the areas of elastin preservation.


CONCLUSIONS
MMP inhibition with BB-94 limited the expansion of AAAs in this rat model. BB-94 appears to work not only as a direct pharmacologic inhibitor of MMPs but also as an interference with the inflammatory response seen in AAAs. Control of the inflammatory response was an unexpected result and may be related to the alterations in feedback mechanisms that are related to extracellular matrix degradation. Because this class of drugs is presently being developed to control the MMP inflammatory response seen with arthritis, these drugs also may ultimately serve as a pharmacologic treatment for patients with AAAs.
Bigatel
D A
DA
Department of Vascular Surgery, Weis Center for Research, Penn State College of Medicine, Danville, PA, USA.
Elmore
J R
JR
Carey
D J
DJ
Cizmeci-Smith
G
G
Franklin
D P
DP
Youkey
J R
JR
D000818:Animals; D000911:Antibodies, Monoclonal; D001012:Aorta, Abdominal / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013876:Thiophenes / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D008666:Metalloendopeptidases