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

ABSTRACT: 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.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 ?-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.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.

SUBMITTER: Dai J

PROVIDER: S-EPMC3089907 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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

Dai Jihong J Zhu Xuemei X Yoder Mervin C MC Wu Yi Y Colman Robert W RW

Arteriosclerosis, thrombosis, and vascular biology 20110120 4

<h4>Objective</h4>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.<h4>Methods and results</h4>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 an ...[more]

PMID: 21252071

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Project description:Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infections an urgent need. We have previously shown that manipulating the lungs' intrinsic host defenses by therapeutic delivery of a unique dyad of pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODNs) with mitochondrial voltage-dependent anion channel 1 (VDAC1) without dependence on Toll-like receptor 9 (TLR9). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), enhances mitochondrial membrane potential (Δ Ψm ), and differentially modulates ETC complex activities. These combined effects promote leak of electrons from ETC complex III, resulting in superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy that has the potential to broadly protect patients against pneumonia during periods of peak vulnerability without reliance on currently available antibiotics.Author summaryPneumonia is a major cause of death worldwide. Increasing antibiotic resistance and expanding immunocompromised populations continue to enhance the clinical urgency to find new strategies to prevent and treat pneumonia. We have identified a novel inhaled therapeutic that stimulates lung epithelial defenses to protect mice against pneumonia in a manner that depends on production of reactive oxygen species (ROS). Here, we report that the induction of protective ROS from lung epithelial mitochondria occurs following the interaction of one component of the treatment, an oligodeoxynucleotide, with the mitochondrial voltage-dependent anion channel 1. This interaction alters energy transfer between the mitochondria and the cytosol, resulting in metabolic reprogramming that drives more electrons into the electron transport chain, then causes electrons to leak from the electron transport chain to form protective ROS. While antioxidant therapies are endorsed in many other disease states, we present here an example of therapeutic induction of ROS that is associated with broad protection against pneumonia without reliance on administration of antibiotics.

Dataset Information

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

Publications

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

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