Department of Life Science and Ewha Research Center for Systems Biology, Ewha Womans University, Seoul 127-750, Korea The Research Center for Cell Homeostasis, Ewha Womans University, Seoul 127-750, Korea.
Department of Life Science and Ewha Research Center for Systems Biology, Ewha Womans University, Seoul 127-750, Korea.
Cardiovasc Res. 2015 Jun 1;106(3):498-508. doi: 10.1093/cvr/cvv130. Epub 2015 Apr 13.
Pro-inflammatory response of vascular smooth muscle cells (VSMCs) is triggered by endothelial damage and a causative step for thrombosis and neointimal thickening in the injured arterial vessels. Therefore, we investigate a role of cytosolic Hsp60 as a novel pro-inflammatory mediator in VSMCs.
Hsp60 was detected in the cytosol of VSMCs. The selective depletion of cytosolic Hsp60 in VSMCs reduced the IκB kinase activation, repressed the induction of nuclear factor (NF)-κB-dependent survival genes (MnSOD and Bfl-1/A1), and enhanced apoptotic death in response to TNF-α. Moreover, a quantitative RNA sequencing revealed that the expression of 75 genes among the 774 TNF-α-inducible genes was significantly reduced by the depletion of cytosolic Hsp60. In particular, the expression of pro-inflammatory cytokines/chemokines, such as CCL2, CCL20, and IL-6, was regulated by the cytosolic Hsp60 in VSMCs. Finally, the depletion of cytosolic Hsp60 markedly inhibited the neointimal thickening in the balloon-injured arterial vessels by inducing apoptotic cell death and inhibiting chemokine production.
This study provides the first evidence that cytosolic Hsp60 could be a therapeutic target for preventing VSMC hyperplasia and inflammatory response in the injured vessels.
血管平滑肌细胞 (VSMC) 的促炎反应是由内皮损伤引发的，是损伤动脉血管中血栓形成和新生内膜增厚的一个致病步骤。因此，我们研究了胞质热休克蛋白 60 (Hsp60) 作为 VSMC 中一种新型促炎介质的作用。
在 VSMC 的细胞质中检测到 Hsp60。VSMC 中胞质 Hsp60 的选择性耗竭减少了 IκB 激酶的激活，抑制了核因子 (NF)-κB 依赖性生存基因 (MnSOD 和 Bfl-1/A1) 的诱导，并增强了对 TNF-α的凋亡死亡。此外，定量 RNA 测序显示，在 774 个 TNF-α诱导的基因中，有 75 个基因的表达因胞质 Hsp60 的耗竭而显著降低。特别是促炎细胞因子/趋化因子的表达，如 CCL2、CCL20 和 IL-6，受 VSMC 中胞质 Hsp60 的调节。最后，胞质 Hsp60 的耗竭通过诱导细胞凋亡和抑制趋化因子的产生，显著抑制了球囊损伤血管的新生内膜增厚。
本研究首次提供了证据表明，胞质 Hsp60 可能是预防损伤血管中 VSMC 增生和炎症反应的治疗靶点。
