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An Integrated Arterial Remodeling Hydrogel for Preventing Restenosis After Angioplasty.

ABSTRACT: The high incidence of restenosis after angioplasty has been the leading reason for the recurrence of coronary heart disease, substantially increasing the mortality risk for patients. However, current anti-stenosis drug-eluting stents face challenges due to their limited functions and long-term safety concerns, significantly compromising their therapeutic effect. Herein, a stent-free anti-stenosis drug coating (denoted as Cur-NO-Gel) based on a peptide hydrogel is proposed. This hydrogel is formed by assembling a nitric oxide (NO) donor-peptide conjugate as a hydrogelator and encapsulating curcumin (Cur) during the assembly process. Cur-NO-Gel has the capability to release NO upon β-galactosidase stimulation and gradually release Cur through hydrogel hydrolysis. The in vitro experiments confirmed that Cur-NO-Gel protects vascular endothelial cells against oxidative stress injury, inhibits cellular activation of vascular smooth muscle cells, and suppresses adventitial fibroblasts. Moreover, periadventitial administration of Cur-NO-Gel in the angioplasty model demonstrate its ability to inhibit vascular stenosis by promoting reendothelialization, suppressing neointima hyperplasia, and preventing constrictive remodeling. Therefore, the study provides proof of concept for designing a new generation of clinical drugs in angioplasty.

SUBMITTER: Fu C

PROVIDER: S-EPMC11022711 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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An Integrated Arterial Remodeling Hydrogel for Preventing Restenosis After Angioplasty.

Fu Chenxing C Li Qiu Q Li Minghui M Zhang Jiexin J Zhou Feiran F Li Zechuan Z He Dongyue D Hu Xinyi X Ning Xiaodong X Guo Wenjie W Li Weirun W Ma Jing J Chen Guoqin G Xiao Yafang Y Ou Caiwen C Guo Weisheng W

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20240211 15

The high incidence of restenosis after angioplasty has been the leading reason for the recurrence of coronary heart disease, substantially increasing the mortality risk for patients. However, current anti-stenosis drug-eluting stents face challenges due to their limited functions and long-term safety concerns, significantly compromising their therapeutic effect. Herein, a stent-free anti-stenosis drug coating (denoted as Cur-NO-Gel) based on a peptide hydrogel is proposed. This hydrogel is forme ...[more]

PMID: 38342624

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Project description:BackgroundTumor necrosis factor-like weak inducer of apoptosis (Tnfsf12; TWEAK) and its receptor Fibroblast growth factor-inducible 14 (Tnfrsf12a; Fn14) participate in the inflammatory response associated with vascular remodeling. However, the functional effect of TWEAK on vascular smooth muscle cells (VSMCs) is not completely elucidated.MethodsNext generation sequencing-based methods were performed to identify genes and pathways regulated by TWEAK in VSMCs. Flow-citometry, wound-healing scratch experiments and transwell migration assays were used to analyze VSMCs proliferation and migration. Mouse wire injury model was done to evaluate the role of TWEAK/Fn14 during neointimal hyperplasia.FindingsTWEAK up-regulated 1611 and down-regulated 1091 genes in VSMCs. Using a gene-set enrichment method, we found a functional module involved in cell proliferation defined as the minimal network connecting top TWEAK up-regulated genes. In vitro experiments in wild-type or Tnfrsf12a deficient VSMCs demonstrated that TWEAK increased cell proliferation, VSMCs motility and migration. Mechanistically, TWEAK increased cyclins (cyclinD1), cyclin-dependent kinases (CDK4, CDK6) and decreased cyclin-dependent kinase inhibitors (p15lNK4B) mRNA and protein expression. Downregulation of p15INK4B induced by TWEAK was mediated by mitogen-activated protein kinase ERK and Akt activation. Tnfrsf12a or Tnfsf12 genetic depletion and pharmacological intervention with TWEAK blocking antibody reduced neointimal formation, decreasing cell proliferation, cyclin D1 and CDK4/6 expression, and increasing p15INK4B expression compared with wild type or IgG-treated mice in wire-injured femoral arteries. Finally, immunohistochemistry in human coronary arteries with stenosis or in-stent restenosis revealed high levels of Fn14, TWEAK and PCNA in VSMCs enriched areas of the neointima as compared with healthy coronary arteries.InterpretationOur data define a major role of TWEAK/Fn14 in the control of VSMCs proliferation and migration during neointimal hyperplasia after wire injury in mice, and identify TWEAK/Fn14 as a potential target for treating in-stent restenosis. FUND: ISCiii-FEDER, CIBERCV and CIBERDEM.

Dataset Information

An Integrated Arterial Remodeling Hydrogel for Preventing Restenosis After Angioplasty.

Publications

An Integrated Arterial Remodeling Hydrogel for Preventing Restenosis After Angioplasty.

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