title: Heat shock protein 90 inhibition by 17-DMAG attenuates abdominal aortic aneurysm formation in mice.
abstract: Abdominal aortic aneurysm (AAA) is a common degenerative vascular disease whose pathogenesis is associated with activation of multiple signaling pathways including Jun NH2-terminal kinases (JNK) and NF-κB. It is now well recognized that these pathways are chaperoned by the heat shock protein 90 (Hsp90), suggesting that inhibition of Hsp90 may be a novel strategy for inhibiting AAAs. The aim of this study is to investigate whether inhibition of Hsp90 by 17-DMAG (17-dimethyl-aminothylamino-17-demethoxy-geldanamycin) attenuates ANG II-induced AAA formation in mice, and, if so, to elucidate the mechanisms involved. Apolipoprotein E-null mice were infused with ANG II to induce AAA formation and simultaneously treated by intraperitoneal injection with either vehicle or 17-DMAG for 4 wk. ANG II infusion induced AAA formation in 80% of mice, which was accompanied by increased matrix metalloproteinase (MMP) activity, enhanced tissue inflammation, oxidative stress, and neovascularization. Importantly, these effects were inhibited by 17-DMAG treatment. Mechanistically, we showed that 17-DMAG prevented the formation and progression of AAA through its inhibitory effects on diverse biological pathways including 1) by blocking ANG II-induced phosphorylation of ERK1/2 and JNK that are critically involved in the regulation of MMPs in vascular smooth muscle cells, 2) by inhibiting IκB kinase expression and expression of MCP-1, and 3) by attenuating ANG II-stimulated angiogenic processes critical to AAA formation. Our results demonstrate that inhibition of Hsp90 by 17-DMAG effectively attenuates ANG II-induced AAA formation by simultaneously inhibiting vascular inflammation, extracellular matrix degradation, and angiogenesis, which are critical in the formation and progression of AAAs.
authors: Department of Pharmacy, Xinhua Hospital, Shanghai Jiaotong University, Shanghai, China; and Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors: Jia
authors: J
authors: Qi
authors: Department of Pharmacy, Xinhua Hospital, Shanghai Jiaotong University, Shanghai, China; and.
authors: Ping
authors: P
authors: Yang
authors: Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors: Bing
authors: B
authors: Yi
authors: Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors: Yan
authors: Y
authors: Huo
authors: Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors: Ming
authors: M
authors: Chen
authors: Department of Pharmacy, Xinhua Hospital, Shanghai Jiaotong University, Shanghai, China; and.
authors: Jian
authors: J
authors: Zhang
authors: Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania jianxin.sun@jefferson.edu.
authors: Jianxin
authors: J
authors: Sun
mesh_terms: D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D001014:Aortic Aneurysm / Q000188:drug therapy* / Q000209:etiology; D001057:Apolipoproteins E / Q000235:genetics; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009389:Neovascularization, Pathologic; D018384:Oxidative Stress
chemical_list: D001057:Apolipoproteins E; D016227:Benzoquinones; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D000804:Angiotensin II; D051550:I-kappa B Kinase; D020782:Matrix Metalloproteinases
keywords: aneurysms; angiotensin II; apolipoprotein E-null mouse; heat shock protein 90
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