Nickel ions from a corroded cardiovascular stent induce monocytic cell apoptosis: Proposed impact on vascular remodeling and mechanism.
OBJECTIVE
Monocytes play important roles in inflammatory responses and vascular remodeling after vascular stenting. This research focused on impacts of nickel (Ni) ions released from a corroded cardiovascular stent on cytotoxicity and monocyte activation.


METHODS
A human promonocytic (macrophage-like) cell line (U937) was exposed to graduated concentrations of Ni(2+)in vitro. Cells were observed and harvested at indicated times to determine the effects using histological and biochemical methods.


RESULTS
Ni caused U937 cell death in dose- and time-dependent manners. In vitro, high concentrations of Ni(2+) (>240 μM) significantly induced cell apoptosis and increased terminal deoxynucleotidyl transferase (TdT) dUTP nick end labeling (TUNEL)-positive cells according to flow cytometric surveillance and triggered apoptotic cell death. Although no significant changes in Bcl-2 or Bax expressions were detected after 24 hours of Ni(2+) treatment, increasing cleavage of caspase-3 and -8 was present. Results showed that cleavage of caspase-8 was inhibited by the presence of the inhibitor, Z-IETD-FMK, and this suggested the presence of Ni(2+)-induced U937 cell death through a death receptor-mediated pathway. Simultaneously, when treated with a high concentration of Ni(2+) ions, expressions of the vascular remodeling factors, matrix metalloproteinases (MMP)-9 and -2, were activated in dose- and time-dependent manners. Secretion of the proliferative factor, monocyte chemoattractant protein (MCP)-1, significantly increased during the first 6 hours of incubation with 480 μM Ni(2+)-treated medium.


CONCLUSIONS
Our results demonstrated that a high concentration of Ni ions causes apoptotic cell death of circulating monocytes. They may also play different roles in vascular remodeling during the corrosion process following implantation of Ni alloy-containing devices.
Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
Chun-Ming
CM
Shih
Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
Chun-Yao
CY
Huang
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiovascular Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
Li-Rung
LR
Liao
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiovascular Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
Chiao-Po
CP
Hsu
Division of Cardiovascular Surgery, Taipei Medical University Hospital, Taipei, Taiwan.
Nai-Wen
NW
Tsao
Institute of Anatomy and Cell Biology, National Yang-Ming University, Taipei, Taiwan.
Hwai-Shi
HS
Wang
Division of Cardiovascular Surgery, Taipei Medical University Hospital, Taipei, Taiwan; Division of Cardiovascular Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
Wei-Yuan
WY
Chen
Division of Cardiovascular Surgery, Taipei Medical University Hospital, Taipei, Taiwan; Division of Cardiovascular Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
Yea-Yang
YY
Su
Division of Cardiovascular Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan.
Shing-Jong
SJ
Lin
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiovascular Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: ccshih@vghtpe.gov.tw.
Chun-Che
CC
Shih
Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan. Electronic address: g870905@tmu.edu.tw.
Feng-Yen
FY
Lin
D017209:Apoptosis / Q000187:drug effects*; D018929:Cell Culture Techniques; D018932:Chemokine CCL2 / Q000378:metabolism; D003343:Corrosion; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004868:Equipment Failure; D006801:Humans; D020287:In Situ Nick-End Labeling; D020782:Matrix Metalloproteinases / Q000378:metabolism; D055017:Monocyte-Macrophage Precursor Cells / Q000187:drug effects*; D009532:Nickel / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015607:Stents / Q000009:adverse effects*; D020298:U937 Cells; D066253:Vascular Remodeling / Q000187:drug effects*
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; D009532:Nickel; D020782:Matrix Metalloproteinases
apoptosis; corrosion; monocyte; nickel; stent