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

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

Research output: Contribution to journalArticle

18 Citations (Scopus)

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
Pages (from-to)883-889
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume31
Issue number4
DOIs
StatePublished - Apr 2011

Fingerprint

High Molecular Weight Kininogens
Cell Aging
Reactive Oxygen Species
Phosphotransferases
Collagen
Galactosidases
Plasma Kallikrein
Kallikrein-Kinin System
Endothelial Progenitor Cells
Telomerase
Giant Cells
Vacuoles
Cell Adhesion
Cell Survival
Endothelial Cells
Phosphorylation
Staining and Labeling

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Cleaved high-molecular-weight kininogen accelerates the onset of endothelial progenitor cell senescence by induction of reactive oxygen species. / Dai, Jihong; Zhu, Xuemei; Yoder, Mervin; Wu, Yi; Colman, Robert W.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 31, No. 4, 04.2011, p. 883-889.

Research output: Contribution to journalArticle

@article{08bc8fe515e0473d953dab487e4f56db,
title = "Cleaved high-molecular-weight kininogen accelerates the onset of endothelial progenitor cell senescence by induction of reactive oxygen species",
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.",
keywords = "aging, endothelial progenitor cells, kininogen, reactive oxygen species, vascular biology",
author = "Jihong Dai and Xuemei Zhu and Mervin Yoder and Yi Wu and Colman, {Robert W.}",
year = "2011",
month = "4",
doi = "10.1161/ATVBAHA.110.222430",
language = "English",
volume = "31",
pages = "883--889",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Cleaved high-molecular-weight kininogen accelerates the onset of endothelial progenitor cell senescence by induction of reactive oxygen species

AU - Dai, Jihong

AU - Zhu, Xuemei

AU - Yoder, Mervin

AU - Wu, Yi

AU - Colman, Robert W.

PY - 2011/4

Y1 - 2011/4

N2 - 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.

AB - 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.

KW - aging

KW - endothelial progenitor cells

KW - kininogen

KW - reactive oxygen species

KW - vascular biology

UR - http://www.scopus.com/inward/record.url?scp=79953738062&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79953738062&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.110.222430

DO - 10.1161/ATVBAHA.110.222430

M3 - Article

C2 - 21252071

AN - SCOPUS:79953738062

VL - 31

SP - 883

EP - 889

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 4

ER -