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A Senolytic-Eluting Coronary Stent for the Prevention of In-Stent Restenosis

Authors
 Cheesue Kim  ;  Seul-Gee Lee  ;  Songhyun Lim  ;  Mungyo Jung  ;  Sung Pil Kwon  ;  Jihye Hong  ;  Mikyung Kang  ;  Hee Su Sohn  ;  Seokhyeong Go  ;  Sangjun Moon  ;  Seung-Jun Lee  ;  Jung-Sun Kim 
Citation
 ACS BIOMATERIALS SCIENCE & ENGINEERING, Vol.8(5) : 1921-1929, 2022-05 
Journal Title
ACS BIOMATERIALS SCIENCE & ENGINEERING
Issue Date
2022-05
MeSH
Animals ; Constriction, Pathologic ; Coronary Restenosis* / prevention & control ; Drug-Eluting Stents* / adverse effects ; Endothelial Cells ; Everolimus / pharmacology ; Hydrogen Peroxide / pharmacology ; Rabbits ; Senotherapeutics ; Stents
Keywords
angioplasty ; cellular senescence ; in-stent restenosis ; senolytic therapy
Abstract
The vast majority of drug-eluting stents (DES) elute either sirolimus or one of its analogues. While limus drugs stymie vascular smooth muscle cell (VSMC) proliferation to prevent in-stent restenosis, their antiproliferative nature is indiscriminate and limits healing of the endothelium in stented vessels, increasing the risk of late-stent thrombosis. Oxidative stress, which is associated with vascular injury from stent implantation, can induce VSMCs to undergo senescence, and senescent VSMCs can produce pro-inflammatory cytokines capable of inducing proliferation of neighboring nonsenescent VSMCs. We explored the potential of senolytic therapy, which involves the selective elimination of senescent cells, in the form of a senolytic-eluting stent (SES) for interventional cardiology. Oxidative stress was modeled in vitro by exposing VSMCs to H2O2, and H2O2-mediated senescence was evaluated by cytochemical staining of senescence-associated β-galactosidase activity and qRT-PCR. Quiescent VSMCs were then treated with the conditioned medium (CM) of H2O2-treated VSMCs. Proliferative effects of CM were analyzed by staining for proliferating cell nuclear antigen. Senolytic effects of the first-generation senolytic ABT263 were observed in vitro, and the effects of ABT263 on endothelial cells were also investigated through an in vitro re-endothelialization assay. SESs were prepared by dip coating. Iliofemoral arteries of hypercholesteremic rabbits were implanted with SES, everolimus-eluting stents (EESs), or bare-metal stents (BMSs), and the area of stenosis was measured 4 weeks post-implantation using optical coherence tomography. We found that a portion of H2O2-treated VSMCs underwent senescence, and that CM of H2O2-treated senescent VSMCs triggered the proliferation of quiescent VSMCs. ABT263 reverted H2O2-mediated senescence and the proliferative capacity of senescent VSMC CM. Unlike everolimus, ABT263 did not affect endothelial cell migration and/or proliferation. SES, but not EES, significantly reduced stenosis area in vivo compared with bare-metal stents (BMSs). This study shows the potential of SES as an alternative to current forms of DES.
Full Text
https://pubs.acs.org/doi/10.1021/acsbiomaterials.1c01611?cookieSet=1
DOI
10.1021/acsbiomaterials.1c01611
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jung Sun(김중선) ORCID logo https://orcid.org/0000-0003-2263-3274
Lee, Seung-Jun(이승준) ORCID logo https://orcid.org/0000-0002-9201-4818
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/188699
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