Abstract P107: Celastrol Supplementation Profoundly Activates Aortic Mmp-9 And Abolishes Sexual Dimorphism Of Abdominal Aortic Aneurysm In Mice.

Abstract

Background and Objective: Abdominal Aortic Aneurysms (AAAs) are permanent dilations of the abdominal aorta with greater than 80% mortality after rupture. AAA prevalence is 4-5 times greater in males than females. AAA formation involves a complex process of destruction of aortic media through degradation of extracellular matrix proteins, elastin and collagen. Angiotensin II (AngII) infusion model of AAA in mice recapitulates major features of human AAA mainly male gender specificity. Celastrol, a pentacyclic triterpene from the root extracts of Thunder God Vine ( Tripterygium wilfordii ), strongly suppressed AngII-induced cardiovascular complications in mice. The purpose of this study is to test the effect of Celastrol supplementation on AngII-induced AAAs in mice. Methods and Results: Male and female LDL receptor -/- mice (8 weeks old; n= 12 per group) were fed a fat-enriched diet (21% wt/wt fat; 0.15% wt/wt cholesterol) supplemented with or without Celastrol (10mg/kg/day) for 5 weeks. After 1 week of diet feeding, mice were infused with AngII (500 or 1000 ng/kg/min) for 28 days by osmotic minipumps. Dietary supplementation of celastrol significantly promoted AngII-induced abdominal aortic luminal dilation (Con = 1.25 ± 0.05 versus Celas = 1.55 ± 0.09 mm, P<0.05) and external aortic width (Con= 1.01 ± 0.09 versus Celas = 1.62 ± 0.14 mm, P<0.05) in male mice as measured by ultra-sonography and ex vivo measurement, with 90% incidence (10/11) compared to 36% (4/11) in control group. Interestingly, celastrol supplementation to AAA female mice, resulted in a significant increase in AngII-induced aortic luminal dilation (Con = 1.17 ± 0.30 versus Celas = 1.57 ± 0.21 mm, P<0.001) and AAA formation (Con= 0.94 ± 0.03 versus Celas = 1.36 ± 0.25 mm, P<0.05) mice with 80% incidence (12/15) compared to 6% (1/15) in control group. Celastrol supplementation dramatically increased AngII-induced aortic leukocyte accumulation, MMP-9 activity and medial elastin degradation in both male and female mice compared to saline and AngII controls. Conclusion: These findings demonstrate that celastrol supplementation to LDLr -/- mice ablates sexual dimorphism and promotes AngII-induced AAA formation, which is associated with increased leukocytic infiltration and MMP-9 activation.