1. Stainless Steel Ions Stimulate Increased Thrombospondin-1-Dependent TGF-Beta Activation by Vascular Smooth Muscle Cells: Implications for In-Stent Restenosis
- Author
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Yiu-Fai Chen, Jack E. Lemons, Peter G. Anderson, Joanne E. Murphy-Ullrich, Manuel A. Pallero, Brigitta C. Brott, and Melissa Talbert Roden
- Subjects
medicine.medical_specialty ,Vascular smooth muscle ,Physiology ,medicine.medical_treatment ,Myocytes, Smooth Muscle ,Prosthesis Design ,Muscle, Smooth, Vascular ,Desmin ,Coronary Restenosis ,Rats, Sprague-Dawley ,Thrombospondin 1 ,Restenosis ,Transforming Growth Factor beta ,medicine ,Cyclic GMP-Dependent Protein Kinases ,Myocyte ,TGF beta Activation ,Animals ,Humans ,cardiovascular diseases ,Angioplasty, Balloon, Coronary ,Cell Shape ,Aorta ,Cells, Cultured ,Thrombospondin ,Chemistry ,Stent ,Hydrogen Peroxide ,equipment and supplies ,medicine.disease ,Catalase ,Stainless Steel ,Coronary Vessels ,Surgery ,Extracellular Matrix ,Rats ,Oxidative Stress ,surgical procedures, operative ,Phenotype ,Cancer research ,Female ,Stents ,Implant ,Cardiology and Cardiovascular Medicine ,Research Paper ,Signal Transduction - Abstract
Background/Aims: Despite advances in stent design, in-stent 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-β is known to be involved in the fibroproliferative responses of vascular smooth muscle cells (VSMCs) in restenosis, and TGF-β antagonists attenuate ISR. We hypothesized that SS ions induce the latent TGF-β activator, thrombospondin-1 (TSP1), through altered oxidative signaling to stimulate increased TGF-β activation and VSMC phenotype change. Methods: VSMCs were treated with SS metal ion cocktails, and morphology, TSP1, extracellular matrix production, desmin and TGF-β activity were assessed by immunoblotting. Results: SS ions stimulate the synthetic phenotype, increased TGF-β 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-β activation.
- Published
- 2009