Premium
Cleaved high molecular weight kininogen stimulates JNK/FOXO4/MnSOD pathway for induction of endothelial progenitor cell senescence
Author(s) -
Zhu Xuemei,
Yang Aizhen,
Xie Zhanli,
Wu Yi
Publication year - 2012
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.26.1_supplement.835.20
Subject(s) - senescence , phosphorylation , high molecular weight kininogen , progenitor cell , stat3 , endothelial progenitor cell , microbiology and biotechnology , blot , kinase , biology , chemistry , stem cell , kininogen , biochemistry , receptor , gene , bradykinin
Recently we have reported that cleaved high molecular weight kininogen (HKa) accelerates the onset of endothelial progenitor cell (EPC) senescence (Arterioscler Thromb Vasc Biol. 2011;31:883), here we explored the underlying mechanisms. It has been known that phosphorylation of transcription factor FOXO4, mediated by c‐Jun N‐terminal kinases (JNK), increases the expression of Mn‐superoxide dismutase (MnSOD), therefore regulating cell senescence. Treatment of human EPCs with 30 nM HKa for 72 hours stimulated JNK phosphorylation at Thr183/Tyr185, and FOXO4 phosphorylation at Thr451, and its effect became the maximum at 100 nM, about 15% of plasma HK level. Concomitantly, as measured by Western blotting and real time PCR, HKa treatment for 72 hours upregulated the expression of MnSOD at protein and mRNA levels in a concentration‐dependent manner. To narrow down the functional domain of HKa, we generated recombinant proteins of human HK heavy chain (HC, 19‐380aa) and light chain (LC, 390‐644aa) and found that HC, but not LC, at 100nM displayed a similar activity with HKa in increasing the percentage of senescent EPCs (63%±6.6 v.s. 77.5%±6.02). Moreover, HC at 100 nM increased FOXO4 phosphorylation at Thr451 and the protein level of MnSOD in EPCs. These results demonstrate that HKa accelerates the onset of EPC senescence, at least in part, by stimulating JNK/FOXO4/MnSOD path way, its effect is mediated by the HC.