PERK Inhibition Promotes Post-angioplasty Re-endothelialization via Modulating SMC Phenotype Changes

Bowen Wang; Mengxue Zhang; Go Urabe; Takuro Shirasu; Lian-Wang Guo; K Craig Kent

doi:10.1016/j.jss.2020.05.070

PERK Inhibition Promotes Post-angioplasty Re-endothelialization via Modulating SMC Phenotype Changes

J Surg Res. 2021 Jan:257:294-305. doi: 10.1016/j.jss.2020.05.070. Epub 2020 Aug 30.

Authors

Bowen Wang¹, Mengxue Zhang², Go Urabe³, Takuro Shirasu⁴, Lian-Wang Guo⁵, K Craig Kent⁶

Affiliations

¹ Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Surgery, College of Medicine, The Ohio State University, Columbus, Ohio; Department of Surgery, School of Medicine, University of Virginia, Charlottesville, Virginia.
² Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Surgery, College of Medicine, The Ohio State University, Columbus, Ohio; Cellular and Molecular Pathology Graduate Program, Department of Pathology, University of Wisconsin-Madison, Madison, Wisconsin.
³ Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Surgery, College of Medicine, The Ohio State University, Columbus, Ohio.
⁴ Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Surgery, College of Medicine, The Ohio State University, Columbus, Ohio; Department of Surgery, School of Medicine, University of Virginia, Charlottesville, Virginia; Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohio.
⁵ Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Surgery, College of Medicine, The Ohio State University, Columbus, Ohio; Department of Surgery, School of Medicine, University of Virginia, Charlottesville, Virginia; Department of Physiology & Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohio. Electronic address: LG8ZR@virginia.edu.
⁶ Department of Surgery, College of Medicine, The Ohio State University, Columbus, Ohio; Department of Surgery, School of Medicine, University of Virginia, Charlottesville, Virginia. Electronic address: CK8AQ@virginia.edu.

Abstract

Background: Drug-eluting stents impair post-angioplasty re-endothelialization thus compromising restenosis prevention while heightening thrombotic risks. We recently found that inhibition of protein kinase RNA-like endoplasmic reticulum kinase (PERK) effectively mitigated both restenosis and thrombosis in rodent models. This motivated us to determine how PERK inhibition impacts re-endothelialization.

Methods: Re-endothelialization was evaluated in endothelial-denuded rat carotid arteries after balloon angioplasty and periadventitial administration of PERK inhibitor in a hydrogel. To study whether PERK in smooth muscle cells (SMCs) regulates re-endothelialization by paracrinally influencing endothelial cells (ECs), denuded arteries exposing SMCs were lentiviral-infected to silence PERK; in vitro, the extracellular vesicles isolated from the medium of PDGF-activated, PERK-upregulating human primary SMCs were transferred to human primary ECs.

Results: Treatment with PERK inhibitor versus vehicle control accelerated re-endothelialization in denuded arteries. PERK-specific silencing in the denuded arterial wall (mainly SMCs) also enhanced re-endothelialization compared to scrambled shRNA control. In vitro, while medium transfer from PDGF-activated SMCs impaired EC viability and increased the mRNA levels of dysfunctional EC markers, either PERK inhibition or silencing in donor SMCs mitigated these EC changes. Furthermore, CXCL10, a paracrine cytokine detrimental to ECs, was increased by PDGF activation and decreased after PERK inhibition or silencing in SMCs.

Conclusions: Attenuating PERK activity pharmacologically or genetically provides an approach to accelerating post-angioplasty re-endothelialization in rats. The mechanism may involve paracrine factors regulated by PERK in SMCs that impact neighboring ECs. This study rationalizes future development of PERK-targeted endothelium-friendly vascular interventions.

Keywords: Angioplasty; Endothelial cell; PERK; Re-endothelialization; Smooth muscle cell.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Angioplasty, Balloon / adverse effects*
Angioplasty, Balloon / instrumentation
Animals
Carotid Arteries / drug effects
Carotid Arteries / pathology
Carotid Arteries / surgery
Coronary Restenosis / etiology
Coronary Restenosis / prevention & control*
Disease Models, Animal
Drug-Eluting Stents / adverse effects
Endothelial Cells / drug effects
Endothelial Cells / pathology
Endothelium, Vascular / cytology
Endothelium, Vascular / drug effects
Endothelium, Vascular / pathology
Humans
Male
Muscle, Smooth, Vascular / cytology
Muscle, Smooth, Vascular / drug effects
Muscle, Smooth, Vascular / pathology
Myocytes, Smooth Muscle / drug effects*
Myocytes, Smooth Muscle / metabolism
Myocytes, Smooth Muscle / pathology
Paracrine Communication / drug effects
Paracrine Communication / genetics
Protein Kinase Inhibitors / administration & dosage*
RNA, Small Interfering / metabolism
Rats
Re-Epithelialization / drug effects*
Re-Epithelialization / genetics
eIF-2 Kinase / antagonists & inhibitors*
eIF-2 Kinase / genetics

Substances

Protein Kinase Inhibitors
RNA, Small Interfering
PERK kinase
eIF-2 Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding