Cytosolic Hsp60 orchestrates the survival and inflammatory responses of vascular smooth muscle cells in injured aortic vessels

Abstract

Aims 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. Methods and results Hsp60 was detected in the cytosol of VSMCs. The selective depletion of cytosolic Hsp60 in VSMCs reduced the I kappa B kinase activation, repressed the induction of nuclear factor (NF)-kappa B-dependent survival genes (MnSOD and Bfl-1/A1), and enhanced apoptotic death in response to TNF-alpha Moreover, a quantitative RNA sequencing revealed that the expression of 75 genes among the 774 TNF-alpha-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. Conclusions 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.