PERK Inhibition Mitigates Restenosis and Thrombosis: A Potential Low-Thrombogenic Antirestenotic Paradigm

Bowen Wang; Mengxue Zhang; Go Urabe; Yitao Huang; Guojun Chen; Debra Wheeler; David J Dornbos 3rd; Allyson Huttinger; Shahid M Nimjee; Shaoqin Gong; Lian-Wang Guo; K Craig Kent

doi:10.1016/j.jacbts.2019.12.005

PERK Inhibition Mitigates Restenosis and Thrombosis: A Potential Low-Thrombogenic Antirestenotic Paradigm

JACC Basic Transl Sci. 2020 Feb 19;5(3):245-263. doi: 10.1016/j.jacbts.2019.12.005. eCollection 2020 Mar.

Authors

Bowen Wang^{1

2}, Mengxue Zhang^{1

3}, Go Urabe^{1

2}, Yitao Huang¹, Guojun Chen⁴, Debra Wheeler⁵, David J Dornbos 3rd⁵, Allyson Huttinger⁵, Shahid M Nimjee⁵, Shaoqin Gong⁴, Lian-Wang Guo^{1

2

6}, K Craig Kent²

Affiliations

¹ Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio.
² Department of Surgery, College of Medicine, The Ohio State University, Columbus, Ohio.
³ Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin.
⁴ Department of Materials Science and Engineering, and Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, Wisconsin.
⁵ Department of Neurosurgery, The Ohio State University Wexner Medical Center, Columbus, Ohio.
⁶ Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohio.

Abstract

Developing endothelial-protective, nonthrombogenic antirestenotic treatments has been a challenge. A major hurdle to this has been the identification of a common molecular target in both smooth muscle cells and endothelial cells, inhibition of which blocks dysfunction of both cell types. The authors' findings suggest that the PERK kinase could be such a target. Importantly, PERK inhibition mitigated both restenosis and thrombosis in preclinical models, implicating a low-thrombogenic antirestenotic paradigm.

Keywords: ATF, activating transcription factor; Ad, adenovirus; CHOP, CCAAT-enhancer-binding protein homologous protein; DES, drug-eluting stents; DMSO, dimethyl sulfoxide; EC, endothelial cell; ER, endoplasmic reticulum; FBS, fetal bovine serum; GFP, green fluorescent protein; HA, hemagglutinin; I/M, intima to media; IEL, internal elastic lamina; IH, intimal hyperplasia; IRE1, inositol-requiring kinase 1; MRTF-A, myocardin related transcription factor A; PDGF, platelet-derived growth factor; PDGF-BB, platelet-derived growth factor with 2 B subunits; PERK; PERK, protein kinase RNA-like endoplasmic reticulum kinase; SMA, smooth muscle actin; SMC, smooth muscle cell; SRF, serum response factor; STAT3, signal transducer and activator of transcription 3; TNF, tumor necrosis factor; eIF2, eukaryotic translation initiation factor 2; endothelial cells; restenosis; siRNA, small interfering ribonucleic acid; smooth muscle cells; thrombosis.

Abstract

Grants and funding