Rapamycin suppresses experimental aortic aneurysm growth.
OBJECTIVE
Inflammatory modulators are important in the pathogenesis of aneurysmal disease. Gene expression profiling of experimental abdominal aortic aneurysm (AAA) tissue demonstrated upregulation of the FK506BP12 (rapamycin binding protein) gene product. Rapamycin is a potent immunosuppressor that prevents recurrent stenosis. However, its effect on aneurysm formation has not been studied. We therefore examined the effect of rapamycin in an experimental rat AAA model.


METHODS
Adult male Wistar rats underwent elastase infusion into isolated infrarenal aortas to create experimental aneurysms. Rats were randomized to receive either rapamycin or placebo via gastric lavage daily starting on the day of surgery. On postoperative day 7 the aneurysm was measured, the infrarenal aorta was harvested, and the rats were euthanized. NF kappa B was measured with Western blotting as a marker of inflammation. Matrix metalloproteinase (MMP)-9 protein levels were measured. Hematoxylin-eosin and elastin staining were used to examine tissue inflammation and elastin preservation.


RESULTS
Aneurysms were significantly smaller in diameter in the rapamycin-treated group (3.3 +/- 0.7 mm vs 4.5 +/- 0.5 mm; P <.0001). NF kappa B levels were significantly reduced by 64% +/- 14% in rapamycin-treated aortas (P =.023). MMP-9 was reduced in rapamycin-treated aortas by 54% +/- 22% (P =.043). Hematoxylin-eosin and elastin staining showed no changes in inflammatory infiltrate or degradation of elastin fibers in elastase-infused aortic segments in rapamycin-treated rats.


CONCLUSIONS
Rapamycin significantly reduces the rate of aneurysm expansion in the experimental AAA rat model by 40%. Biochemical evidence suggests that this is related to suppression of inflammatory signaling and decreased MMP-9 levels. Rapamycin could provide a new treatment for small aneurysms.


CONCLUSIONS
Human aortic aneurysms are characterized histologically by an inflammatory infiltrate with severe proteolytic destruction. Rapamycin is an immunosuppressive agent commonly used to control transplant rejection and intimal hyperplasia by modulating the inflammatory cascade. In this experimental model rapamycin suppressed aneurysm expansion, decreased NF kappa B activation (a marker of inflammation), and decreased matrix metalloproteinase-9 levels. It is hoped that rapamycin or other similar anti-inflammatory drugs will one day be able to control aneurysm expansion in patients
Lawrence
David M
DM
Section of Vascular Surgery and Weis Center for Research, Geisinger Clinic, Danville, PA 17822, USA.
Singh
Robert S
RS
Franklin
David P
DP
Carey
David J
DJ
Elmore
James R
JR
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000276:immunology; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D018450:Disease Progression; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000276:immunology; D023421:Models, Animal; D016328:NF-kappa B / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000008:administration & dosage*
D007166:Immunosuppressive Agents; D016328:NF-kappa B; D020780:Matrix Metalloproteinase 9; D020123:Sirolimus