Raizman Joshua E, Chen Yong-Xiang, Seibert Tara, Hibbert Benjamin, Cuerrier Charles M, Salari Samira, Zhao Xiaoling, Hu Tieqiang, Shi Chunhua, Ma Xiaoli, Simard Trevor, Caravaggio Justin, Rayner Katey, Bowdish Dawn, Moore Kathryn, O'Brien Edward R
University of Ottawa Heart Institute, Ottawa, Canada.
Biochim Biophys Acta. 2013 Dec;1831(12):1721-8. doi: 10.1016/j.bbalip.2013.07.015. Epub 2013 Aug 11.
Previously, we showed an inverse correlation between HSP27 serum levels and experimental atherogenesis in ApoE(-/-) mice that over-express HSP27 and speculated that the apparent binding of HSP27 to scavenger receptor-A (SR-A) was of mechanistic importance in attenuating foam cell formation. However, the nature and importance of the interplay between HSP27 and SR-A in atheroprotection remained unclear. Treatment of THP-1 macrophages with recombinant HSP27 (rHSP27) inhibited acLDL binding (-34%; p<0.005) and uptake (-38%, p<0.05). rHSP27 reduced SR-A mRNA (-39%, p=0.02), total protein (-56%, p=0.01) and cell surface (-53%, p<0.001) expression. The reduction in SR-A expression by rHSP27 was associated with a 4-fold increase in nuclear factor-kappa B (NF-κB) signaling (p<0.001 versus control), while an inhibitor of NF-κB signaling, BAY11-7082, attenuated the negative effects of rHSP27 on both SR-A expression and lipid uptake. To determine if SR-A is required for HSP27 mediated atheroprotection in vivo, ApoE(-/-) and ApoE(-/-) SR-A(-/-) mice fed with a high fat diet were treated for 3weeks with rHSP25. Compared to controls, rHSP25 therapy reduced aortic en face and aortic sinus atherosclerotic lesion size in ApoE(-/-) mice by 39% and 36% (p<0.05), respectively, but not in ApoE(-/-)SR-A(-/-) mice. In conclusion, rHSP27 diminishes SR-A expression, resulting in attenuated foam cell formation in vitro. Regulation of SR-A by HSP27 may involve the participation of NF-κB signaling. Lastly, SR-A is required for HSP27-mediated atheroprotection in vivo.
此前，我们发现，在过表达热休克蛋白27（HSP27）的载脂蛋白E基因敲除（ApoE(-/-)）小鼠中，血清HSP27水平与实验性动脉粥样硬化呈负相关，并推测HSP27与清道夫受体A（SR-A）的明显结合在减弱泡沫细胞形成中具有重要机制意义。然而，HSP27与SR-A在动脉粥样硬化保护中的相互作用的性质和重要性仍不清楚。用重组HSP27（rHSP27）处理THP-1巨噬细胞可抑制乙酰化低密度脂蛋白（acLDL）结合（-34%；p<0.005）和摄取（-38%，p<0.05）。rHSP27降低了SR-A信使核糖核酸（mRNA）水平（-39%，p=0.02）、总蛋白水平（-56%，p=0.01）和细胞表面表达（-53%，p<0.001）。rHSP27导致的SR-A表达降低与核因子-κB（NF-κB）信号传导增加4倍有关（与对照相比，p<0.001），而NF-κB信号传导抑制剂BAY11-7082减弱了rHSP27对SR-A表达和脂质摄取的负面影响。为了确定在体内HSP27介导的动脉粥样硬化保护是否需要SR-A，给喂食高脂饮食的ApoE(-/-)和ApoE(-/-) SR-A(-/-)小鼠用rHSP25治疗3周。与对照组相比，rHSP25治疗使ApoE(-/-)小鼠的主动脉整体和主动脉窦动脉粥样硬化病变大小分别减少了39%和36%（p<0.05），但在ApoE(-/-)SR-A(-/-)小鼠中未减少。总之，rHSP减少了SR-A表达，导致体外泡沫细胞形成减弱。HSP27对SR-A的调节可能涉及NF-κB信号传导的参与。最后，在体内HSP27介导的动脉粥样硬化保护需要SR-A。
