Elevated Heat Shock Protein 27 levels predict relative freedom from cardiovascular events. In ApoE-/- mice HSP27 over-expression or twice daily subcutaneous injections reduce blood and plaque cholesterol levels, inflammation and atherogenesis. While natural antibodies to HSP27 are present in human blood their role is unknown. Here, we show that blood levels of both HSP27 and anti-HSP27 IgG antibodies are elevated in healthy controls compared to patients with cardiovascular disease. ApoE-/- mice vaccinated with recombinant HSP25 (murine ortholog) develop elevated anti-HSP25 IgG antibodies and reduced levels of cholesterol, inflammation and atherosclerosis. The effects on cholesterol metabolism were divergent: increased hepatic LDLR expression and reduced plasma PCSK9 levels. In vitro, a polyclonal anti-HSP27 IgG antibody combined with rHSP27 to upregulate hepatocyte LDLR expression via an NF-kB-dependent pathway that is independent of SREBP2 expression and intracellular cholesterol levels. HSP27 immunotherapy represents a novel means of lowering not only cholesterol but also PCSK9.

中文翻译：

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热激蛋白27免疫复合物上调LDLR表达从而减少血浆胆固醇和动脉粥样硬化

热休克蛋白27水平升高可预测相对不受心血管事件的影响。在ApoE-/-小鼠中，HSP27过表达或每天两次皮下注射可降低血液和斑块胆固醇水平，炎症和动脉粥样硬化。虽然人类血液中存在针对HSP27的天然抗体，但其作用尚不清楚。在这里，我们显示与心血管疾病患者相比，健康对照组的HSP27和抗HSP27 IgG抗体的血液水平均升高。接种了重组HSP25（鼠直向同源物）的ApoE-/-小鼠可产生升高的抗HSP25 IgG抗体，并降低胆固醇，炎症和动脉粥样硬化的水平。对胆固醇代谢的影响各不相同：肝LDLR表达增加，血浆PCSK9水平降低。体外，多克隆抗HSP27 IgG抗体与rHSP27结合，通过NF-kB依赖性途径上调肝细胞LDLR表达，而该途径与SREBP2表达和细胞内胆固醇水平无关。HSP27免疫疗法代表了一种不仅降低胆固醇而且降低PCSK9的新颖方法。