Author + information
- Received June 19, 2019
- Revision received December 13, 2019
- Accepted December 13, 2019
- Published online March 23, 2020.
- Bowen Wang, PhDa,b,∗,
- Mengxue Zhang, MD, PhDa,c,∗,
- Go Urabe, MD, PhDa,b,
- Yitao Huang, BSa,
- Guojun Chen, PhDd,
- Debra Wheeler, BSe,
- David J. Dornbos III, MDe,
- Allyson Huttinger, BSe,
- Shahid M. Nimjee, MD, PhDe,
- Shaoqin Gong, PhDd,
- Lian-Wang Guo, PhDa,b,f,∗∗ ( and )
- K. Craig Kent, MDb,∗ ()
- aDavis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio
- bDepartment of Surgery, College of Medicine, The Ohio State University, Columbus, Ohio
- cCellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin
- dDepartment of Materials Science and Engineering, and Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, Wisconsin
- eDepartment of Neurosurgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
- fDepartment of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohio
- ↵∗Address for correspondence:
Dr. K. Craig Kent, Department of Surgery, College of Medicine; Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, 410 West 10th Avenue, Columbus, Ohio 43210.
- ↵∗∗Dr. Lian-Wang Guo, Department of Surgery and Department of Physiology & Cell Biology, The Ohio State University, 473 West 12th Avenue, Columbus, Ohio 43210.
• Drug-eluting stents impede neointimal smooth muscle cell hyperplasia but exacerbate endothelial cell dysfunction and thrombogenicity. It has been a challenge to identify a common target to inhibit both. Findings in this study suggest PERK as such a target.
• A PERK inhibitor administered either via an endovascular (in biomimetic nanocarriers) or perivascular (in hydrogel) route effectively mitigated neointimal hyperplasia in rats.
• Oral gavage of the PERK inhibitor partially preserved the normal blood flow in a mouse model of induced thrombosis.
• Dampening PERK activity inhibited STAT3 while activating SRF in smooth muscle cells, and also reduced prothrombogenic tissue factor and growth impairment of endothelial cells.
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.
↵∗ Drs. Wang and Zhang contributed equally to this work and are joint first authors.
This work was supported by National Institutes of Health grants R01HL143469, R01HL129785 (to Drs. Gong, Guo, and Kent), R01HL133665 (to Dr. Guo), K25CA166178 (to Dr. Gong), and American Heart Association pre-doctoral awards 17PRE33670865 (to Dr. Zhang) and 16PRE30160010 (to Dr. Wang). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received June 19, 2019.
- Revision received December 13, 2019.
- Accepted December 13, 2019.
- 2020 The Authors