Abstract 99: Rosiglitazone Negatively Regulates C-jun N-terminal Kinase and Toll-like Receptor 4 Proinflammatory Signaling During Initiation of Experimental Aortic Aneurysms
Objective: Development and rupture of aortic aneurysms (AA) is a complex process involving inflammation, cell death, tissue and matrix remodeling. The thiazolidinediones (TZDs) including Rosiglitazone (RGZ) are a family of drugs which act as agonists of the nuclear peroxisome proliferator-activated receptors and have a broad spectrum of effects on a number of biological processes in the cardiovascular system. In our previous study we have demonstrated that RGZ has a marked effect on both aneurysm rupture and development, however, the precise mechanism of this is unknown.
Methods and Results: In the present study, we examined possible targets of RGZ action in the early stages of Angiotensin II-induced AA in apolipoprotein E-deficient mice. For this purpose we employed immunoblotting, ELISA and antibody array approaches. We found that RGZ significantly inhibited c-Jun N-terminal kinase (JNK) phosphorylation and down-regulated toll-like receptor 4 (TLR4) expression at the site of lesion formation in response to Angiotensin II infusion in the initiation stage (6-72h) of experimental AA development. Importantly, this effect was also associated with a dramatic reduction in production of TLR4/JNK-dependent proinflammatory chemokines MCP-1 and MIP-1α.
Conclusion: These data suggest that RGZ can modulate inflammatory processes by blocking TLR4/JNK signalling in initiation stages of AA development.
- © 2012 by American Heart Association, Inc.