PERK Inhibition Mitigates Restenosis and Thrombosis
| Autor: | Yitao Huang, Shahid M Nimjee, Go Urabe, Debra G Wheeler, David J. Dornbos, Bowen Wang, Allyson Huttinger, Guojun Chen, Mengxue Zhang, Lian-Wang Guo, K. Craig Kent, Shaoqin Gong |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
STAT3 signal transducer and activator of transcription 3 Cell SMC smooth muscle cell DMSO dimethyl sulfoxide 030204 cardiovascular system & hematology ATF activating transcription factor PDGF platelet-derived growth factor PRECLINICAL RESEARCH 0302 clinical medicine siRNA small interfering ribonucleic acid Restenosis PDGF-BB platelet-derived growth factor with 2 B subunits I/M intima to media GFP green fluorescent protein Neointimal hyperplasia TNF tumor necrosis factor Ad adenovirus Hyperplasia Thrombosis endothelial cells smooth muscle cells 3. Good health Endothelial stem cell IRE1 inositol-requiring kinase 1 medicine.anatomical_structure SMA smooth muscle actin Cardiology and Cardiovascular Medicine PERK endocrine system Thrombogenicity IEL internal elastic lamina CHOP CCAAT-enhancer-binding protein homologous protein eIF2 eukaryotic translation initiation factor 2 ER endoplasmic reticulum MRTF-A myocardin related transcription factor A restenosis IH intimal hyperplasia 03 medical and health sciences Tissue factor FBS fetal bovine serum medicine DES drug-eluting stents thrombosis EC endothelial cell business.industry PERK protein kinase RNA-like endoplasmic reticulum kinase medicine.disease SRF serum response factor 030104 developmental biology Cancer research business HA hemagglutinin |
| Zdroj: | JACC: Basic to Translational Science |
| ISSN: | 2452-302X |
| DOI: | 10.1016/j.jacbts.2019.12.005 |
| Popis: | Visual Abstract Highlights • 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. Summary 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. |
| Databáze: | OpenAIRE |
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