Heat shock protein 90 inhibition by 17-DMAG attenuates abdominal aortic aneurysm formation in mice
Heat shock protein 90 inhibition by 17-DMAG attenuates abdominal aortic aneurysm formation in mice
复制标题
17-DMAG 抑制热休克蛋白 90 可减轻小鼠腹主动脉瘤形成
DOI：
10.1152/ajpheart.00470.2014
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发表时间：
2015-04-15
影响因子：
4.8
通讯作者：
Sun, Jianxin
中科院分区：
文献类型：
--
作者：
Qi, Jia;Yang, Ping;Sun, Jianxin
腹主动脉瘤（AAA）是一种常见的退行性血管疾病，其发病机制与包括Jun氨基末端激酶（JNK）和NF-κ B B在内的多种信号通路的激活有关。现在已经认识到这些途径是由热休克蛋白90（Hsp 90）陪伴的，这表明抑制Hsp 90可能是抑制AAAs的新策略。本研究的目的是研究17-DMAG（17-dimethyl-aminothylamino-17-demethoxy-geldanamycin）抑制Hsp 90是否能减弱ANG II诱导的小鼠AAA形成，如果是，则阐明相关机制。将载脂蛋白E缺失小鼠输注ANG II以诱导AAA形成，同时通过腹腔内注射载体或17-DMAG治疗4周。ANG II输注诱导80%的小鼠AAA形成，伴随基质金属蛋白酶（MMP）活性增加，组织炎症增强，氧化应激和新血管形成。重要的是，这些作用被17-DMAG处理抑制。从机制上讲，我们表明17-DMAG通过其对多种生物学途径的抑制作用来预防AAA的形成和进展，包括1）通过阻断ANG II诱导的ERK 1/2和JNK的磷酸化，ERK 1/2和JNK在血管平滑肌细胞中的MMP调节中起关键作用，2）通过抑制I κ B激酶表达和MCP-1表达，和3）通过减弱对AAA形成至关重要的ANG II刺激的血管生成过程。我们的研究结果表明，抑制Hsp 90的17-DMAG有效地减弱ANG II诱导的AAA的形成，同时抑制血管炎症，细胞外基质降解和血管生成，这是至关重要的AAA的形成和发展。
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-kappa B. 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 I kappa B 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.