title: Rosiglitazone negatively regulates c-Jun N-terminal kinase and toll-like receptor 4 proinflammatory signalling during initiation of experimental aortic aneurysms.
abstract: OBJECTIVE
  Development and rupture of aortic aneurysms (AA) is a complex process involving inflammation, cell death, tissue and matrix remodelling. 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.
  
  
  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 (6-72 h) of experimental AA development. Importantly, this effect was also associated with a decrease of CD4 antigen and reduction in production of TLR4/JNK-dependant proinflammatory chemokines MCP-1 and MIP-1α.
  
  
  CONCLUSIONS
  These data suggest that RGZ can modulate inflammatory processes by blocking TLR4/JNK signalling in initiation stages of AA development.
authors.affiliation: Division of Clinical Sciences, St. George's University of London, London, UK.
authors.forename: Grisha
authors.initials: G
authors.lastname: Pirianov
authors.forename: Evelyn
authors.initials: E
authors.lastname: Torsney
authors.forename: Franklyn
authors.initials: F
authors.lastname: Howe
authors.forename: Gillian W
authors.initials: GW
authors.lastname: Cockerill
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001014:Aortic Aneurysm / Q000139:chemically induced* / Q000517:prevention & control; D001019:Aortic Rupture / Q000517:prevention & control; D015536:Down-Regulation; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D045162:Thiazolidinediones; D051197:Toll-Like Receptor 4; D000077154:Rosiglitazone; D000804:Angiotensin II; D048031:JNK Mitogen-Activated Protein Kinases