Stainless steel ions stimulate increased thrombospondin-1-dependent TGF-beta activation by vascular smooth muscle cells: implications for in-stent restenosis.
OBJECTIVE
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-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.
Pallero
Manuel A
MA
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
Talbert Roden
Melissa
M
Chen
Yiu-Fai
YF
Anderson
Peter G
PG
Lemons
Jack
J
Brott
Brigitta C
BC
Murphy-Ullrich
Joanne E
JE
D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects / Q000295:instrumentation*; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D002374:Catalase / Q000378:metabolism; D048430:Cell Shape; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D003893:Desmin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010641:Phenotype; D011474:Prosthesis Design; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013193:Stainless Steel; D015607:Stents; D019700:Thrombospondin 1 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D003893:Desmin; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D013193:Stainless Steel; D006861:Hydrogen Peroxide; D002374:Catalase; D017869:Cyclic GMP-Dependent Protein Kinases