Journal
JOURNAL OF VASCULAR RESEARCH
Volume 47, Issue 4, Pages 309-322Publisher
KARGER
DOI: 10.1159/000265565
Keywords
Restenosis; Smooth muscle cells; TGF-beta; Thrombospondin-1; Stent corrosion; Hydrogen peroxide
Categories
Funding
- NIH [HL079644, DK078038, C06 RR 15490, HL080017, HL044195, F30DE018259]
- NIBIB-BRP [EB001715]
- NATIONAL CENTER FOR RESEARCH RESOURCES [C06RR015490] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL079644, R01HL044195, R01HL080017] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [R01EB001715] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH [F30DE018259] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK078038, R01DK060658] Funding Source: NIH RePORTER
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Background/Aims: Despite advances in stent design, instent restenosis (ISR) remains a significant clinical problem. All implant metals exhibit corrosion, which results in release of metal ions. Stainless steel (SS), a metal alloy widely used in stents, releases ions to the vessel wall and induces reactive oxygen species, inflammation and fibroproliferative responses. The molecular mechanisms are unknown. TGF-beta is known to be involved in the fibroproliferative responses of vascular smooth muscle cells (VSMCs) in restenosis, and TGF-beta antagonists attenuate ISR. We hypothesized that SS ions induce the latent TGF-beta activator, thrombospondin-1 (TSP1), through altered oxidative signaling to stimulate increased TGF-beta activation and VSMC phenotype change. Methods: VSMCs were treated with SS metal ion cocktails, and morphology, TSP1, extracellular matrix production, desmin and TGF-beta activity were assessed by immunoblotting. Results: SS ions stimulate the synthetic phenotype, increased TGF-beta activity, TSP1, increased extracellular matrix and downregulation of desmin in VSMCs. Furthermore, SS ions increase hydrogen peroxide and decrease cGMP-dependent protein kinase (PKG) signaling, a known repressor of TSP1 transcription. Catalase blocks SS ion attenuation of PKG signaling and increased TSP1 expression. Conclusions: These data suggest that ions from stent alloy corrosion contribute to ISR through stimulation of TSP1-dependent TGF-beta activation. Copyright (C) 2009 S. Karger AG, Basel
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