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Cleaved high molecular weight kininogen induces endothelial progenitor cell senescence in a ROS‐‐p38MAPK‐ p16INK4a signaling pathway and inhibits their vascular repair capacity
Author(s) -
Dai Jihong,
Wu Yi
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.616.15
Subject(s) - progenitor cell , endothelial progenitor cell , high molecular weight kininogen , microbiology and biotechnology , senescence , kininogen , progenitor , chemistry , biology , stem cell , biochemistry , bradykinin , receptor
Objective We recently reported cleaved high molecular weight kininogen (HKa), a major plasma kallikrein‐kinin system (KKS) activation product, inhibits vasculogenic differentiation of endothelial progenitor cell ( EPCs) and accelerates their senescence (J Thromb Haemost 2010;8:185–93, FASEB J 2010;24:750.10). We further investigated the molecular mechanism for HKa induction of EPC senescence and examined the in vivo effect of HKa on EPCs. Methods and Results After treatment with HKa, EPCs displayed typical senescent morphology. HKa inhibited telomerase activity of EPCs, accompanied by an increase in the acidic β‐galactosidase‐positive cells. HKa enhanced p38 kinase phosphorylation and prosenescence molecule p16 INK4a expression. Correspondingly, SB203580, a p38 inhibitor, attenuated HKa‐induced p16 INK4a expression and EPC senescence. Either N‐Acetyl‐Cysteine or Mn(III)tetrakis(4‐Benzoic acid)porphyrin Chloride, scavenger of reactive oxygen species (ROS), prevented HKa induction of EPC senescence. In a rat carotid artery injury model, HKa, administered into Lewis rats for 7 days, significantly suppressed the incorporation of exogenous EPCs into the denuded endothelium and delayed the reendothelialization. Conclusions HKa induces EPC senescence by activating the ROS ‐ p38 kinase ‐ p16 INK4a signaling cascade. The plasma KKS activation is possibly associated with EPC dysfunction.