Vascular Research Lab, IIS, Fundación Jiménez Díaz, Autónoma University, Av. Reyes Católicos 2, 28040 Madrid, Spain.
Cardiovasc Res. 2010 May 1;86(2):330-7. doi: 10.1093/cvr/cvq046. Epub 2010 Feb 12.
Heat shock protein 90 (HSP90) is a ubiquitous chaperone involved in the folding, activation, and assembly of many proteins. HSP90 inhibitors [17-allylamino-17-demethoxygeldamycin (17-AAG)/17-dimethyl aminothylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG)] bind to and inactivate HSP90, increasing the heat shock response and suppressing different signalling pathways. We aim to investigate the effect of HSP90 inhibitors in the modulation of inflammatory responses during atherogenesis.
In human atherosclerotic plaques, HSP90 immunostaining was increased in inflammatory regions and in plaques characterized by lower cap thickness. In cultured human macrophages and vascular smooth muscle cells, treatment with either 17-AAG or 17-DMAG increased HSP70 expression and reduced transcription factor [signal transducers and activators of transcription (STAT) and nuclear factor-kappaB (NF-kappaB)] activation and chemokine expression induced by proinflammatory cytokines. In vivo, hyperlipidaemic ApoE(-/-) mice were randomized to 17-DMAG (2 mg/kg every 2 days, n = 11) or vehicle injected (n = 9) during 10 weeks. Atherosclerotic plaques of mice treated with 17-DMAG displayed increased HSP70 expression and diminished NF-kappaB and STAT activation, along with decreased lesion, lipid, and macrophage content, compared with vehicle-injected mice. In addition, treatment with 17-DMAG significantly reduced monocyte chemoattractant protein-1 levels, both in plaques and in plasma.
HSP90 expression is associated with features of plaque instability in advanced human lesions. HSP90 inhibitors reduce inflammatory responses in atherosclerosis, suggesting that HSP90 could be a novel therapeutic target in atherosclerosis.
热休克蛋白 90（HSP90）是一种普遍存在的伴侣蛋白，参与许多蛋白质的折叠、激活和组装。HSP90 抑制剂[17-烯丙基-17-去甲氧基格尔德霉素（17-AAG）/17-二甲基氨基乙基-17-去甲氧基格尔德霉素盐酸盐（17-DMAG）]与 HSP90 结合并使其失活，增加热休克反应并抑制不同的信号通路。我们旨在研究 HSP90 抑制剂在动脉粥样硬化过程中炎症反应调节中的作用。
在人类动脉粥样硬化斑块中，HSP90 免疫染色在炎症区域和帽厚度较低的斑块中增加。在培养的人巨噬细胞和血管平滑肌细胞中，用 17-AAG 或 17-DMAG 处理可增加 HSP70 表达，并减少促炎细胞因子诱导的转录因子[信号转导和转录激活因子（STAT）和核因子-kappaB（NF-kappaB）]激活和趋化因子表达。在体内，高脂血症 ApoE（-/-）小鼠随机分为 17-DMAG（2 mg/kg，每 2 天一次，n = 11）或载体注射（n = 9）组，治疗 10 周。与载体注射小鼠相比，用 17-DMAG 治疗的小鼠的动脉粥样硬化斑块显示 HSP70 表达增加，NF-kappaB 和 STAT 激活减少，病变、脂质和巨噬细胞含量减少，此外，17-DMAG 治疗还显著降低了斑块和血浆中的单核细胞趋化蛋白-1 水平。
HSP90 表达与人类晚期病变不稳定斑块的特征有关。HSP90 抑制剂可减少动脉粥样硬化中的炎症反应，提示 HSP90 可能成为动脉粥样硬化的新治疗靶点。
