Cleaved high-molecular-weight kininogen accelerates the onset of endothelial progenitor cell senescence by induction of reactive oxygen species

Jihong Dai, Xuemei Zhu, Mervin C. Yoder, Yi Wu, Robert W. Colman

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Objective- Cleaved high-molecular-weight kininogen (HKa), an activation product of the plasma kallikrein-kinin system, inhibits endothelial cell functions. We questioned whether HKa affects the function of endothelial progenitor cells (EPCs) and accelerates their senescence. Methods and Results- Treatment with HKa for 2 weeks markedly inhibited the formation of large colonies and proliferation of EPCs on collagen surfaces, whereas HKa did not affect collagen-mediated EPC adhesion and survival. Concomitantly, treated EPCs displayed flattened and giant cell morphological changes and formation of intracellular vacuoles. As determined by acidic β-galactosidase staining, HKa increased senescent EPCs by 2- and >3-fold after culture for 1 and 2 weeks, respectively. In addition, HKa suppressed the telomerase activity of EPCs. HKa concentration-dependently increased the generation of intracellular reactive oxygen species (ROS) and markedly upregulated p38 kinase phosphorylation and prosenescence molecule p16 INK4a expression. SB203580, a p38 inhibitor, attenuated the level of HKa-enhanced p16 INK4a expression. Either quenching of ROS or inhibition of p38 kinase prevented HKa-induced EPC senescence. Conclusion- HKa accelerates the onset of EPC senescence by activating the ROS-p38 kinase-p16 INK4a signaling cascade. This novel activity of HKa points out the likelihood of HKa serving as an endogenous inducer of EPC senescence.

Original languageEnglish (US)
Pages (from-to)883-889
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume31
Issue number4
DOIs
StatePublished - Apr 1 2011

Keywords

  • aging
  • endothelial progenitor cells
  • kininogen
  • reactive oxygen species
  • vascular biology

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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