Identification of endothelial protein C receptor as a novel druggable agonistic target for reendothelialization promotion and thrombosis prevention of eluting stent
Year: 2024
Type: article
Abstract: The commercially available drug-eluting stent with limus (rapamycin, everolimus, etc.) or paclitaxel inhibits smooth muscle cell (SMC), reducing the in-stent restenosis, whereas damages endothelial cell (EC) and delays stent reendothelialization, increasing the risk of stent thrombosis (ST) and sudden cardiac death. Here we present a new strategy for promoting stent reendothelialization and preventing ST by exploring the application of precise molecular targets with EC specificity. Proteomics was used to investigate the molecular mechanism of EC injury caused by rapamycin. Endothelial protein C receptor (EPCR) was screened out as a crucial EC-specific effector. Limus and paclitaxel repressed the EPCR expression, while overexpression of EPCR protected EC from coating (eluting) drug-induced injury. Furthermore, the ligand activated protein C (APC), polypeptide TR47, and compound parmodulin 2, which activated the target EPCR, promoted EC functions and inhibited platelet or neutrophil adhesion, and enhanced rapamycin stent reendothelialization in the simulated stent environment and in vitro. In vivo, the APC/rapamycin-coating promoted reendothelialization rapidly and prevented ST more effectively than rapamycin-coating alone, in both traditional metal stents and biodegradable stents. Additionally, overexpression or activation of the target EPCR did not affect the cellular behavior of SMC or the inhibitory effect of rapamycin on SMC. In conclusion, EPCR is a promising therapeutical agonistic target for pro-reendothelialization and anti-thrombosis of eluting stent. Activation of EPCR protects against coating drugs-induced EC injury, inflammatory cell, or platelet adhesion onto the stent. The novel application formula for APC/rapamycin-combined eluting promotes stent reendothelialization and prevents ST.
Source: Bioactive Materials
Authors: Jing Chen, Changyi Zhou, Weilun Fang, Jiasheng Yin, Jian Shi, Junbo Ge, Li Shen, Shi-Ming Liu, Shao-Jun Liu
Institutions: Guangzhou University of Chinese Medicine, Second Affiliated Hospital of Guangzhou Medical University, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou Medical University, Chinese Academy of Medical Sciences & Peking Union Medical College, Fudan University, Zhongshan Hospital
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,200
Funders: Guangzhou Medical University, National Natural Science Foundation of China, National Aerospace Science Foundation of China, Guangzhou Science, Technology and Innovation Commission, Discipline and Specialty, and Construction Foundation of Colleges and Universities of Guangdong Province, Foundation for Innovation Groups of Basic Research in Gansu Province, Basic and Applied Basic Research Foundation of Guangdong Province
OpenAlex ID: W4401454785