Boae Choi1, Mina Choi1, Charny Park2, Eun Kyung Lee1, Dong Hoon Kang1, Doo Jae Lee1, Jae Yoon Yeom1, Yeonjoo Jung2, Jaesang Kim2, Sanghyuk Lee3, Sang Won Kang4. 1. 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. 2. Department of Life Science and Ewha Research Center for Systems Biology, Ewha Womans University, Seoul 127-750, Korea. 3. Department of Life Science and Ewha Research Center for Systems Biology, Ewha Womans University, Seoul 127-750, Korea sanghyuk@ewha.ac.kr kangsw@ewha.ac.kr. 4. 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 sanghyuk@ewha.ac.kr kangsw@ewha.ac.kr.
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 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. 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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 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. 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Joseph W Hawkins; Madeleine C McNeill; Reza Ebrahimighaei; Harry H Mellor; Andrew C Newby; Mark Bond Journal: Cells Date: 2022-04-21 Impact factor: 7.666