Document Detail

Endonuclease G mediates endothelial cell death induced by carbamylated LDL.
MedLine Citation:
PMID:  21460199     Owner:  NLM     Status:  MEDLINE    
End-stage kidney disease is a terminal stage of chronic kidney disease, which is associated with a high incidence of cardiovascular disease. Cardiovascular disease frequently results from endothelial injury caused by carbamylated LDL (cLDL), the product of LDL modification by urea-derived cyanate. Our previous data suggested that cLDL induces mitogen-activated protein kinase-dependent mitotic DNA fragmentation and cell death. However, the mechanism of this pathway is unknown. The current study demonstrated that cLDL-induced endothelial mitotic cell death is independent of caspase-3. The expression of endonuclease G (EndoG), the nuclease implicated in caspase-independent DNA fragmentation, was significantly increased in response to cLDL exposure to the cells. The inhibition of EndoG by RNAi protected cLDL-induced DNA fragmentation, whereas the overexpression of EndoG induced more DNA fragmentation in endothelial cells. Ex vivo experiments with primary endothelial cells isolated from wild-type (WT) and EndoG knockout (KO) mice demonstrated that EndoG KO cells are partially protected against cLDL toxicity compared with WT cells. To determine cLDL toxicity in vivo, we administered cLDL or native LDL (nLDL) intravenously to the WT and EndoG KO mice and then measured floating endothelial cells in blood using flow cytometry. The results showed an increased number of floating endothelial cells after cLDL versus nLDL injection in WT mice but not in EndoG KO mice. Finally, the inhibitors of MEK-ERK1/2 and JNK-c-jun pathways decreased cLDL-induced EndoG overexpression and DNA fragmentation. In summary, our data suggest that cLDL-induced endothelial toxicity is caspase independent and results from EndoG-dependent DNA fragmentation.
Eugene O Apostolov; Debarti Ray; Wilson M Alobuia; Marina V Mikhailova; Xiaoying Wang; Alexei G Basnakian; Sudhir V Shah
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-04-01
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  300     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-02     Completed Date:  2011-08-23     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1997-2004     Citation Subset:  IM    
Dept. of Pharmacology & Toxicology, Univ. of Arkansas for Medical Sciences, 4301 W. Markham St., Slot 638, Little Rock, AR 72205, USA.
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MeSH Terms
Apoptosis / drug effects*,  physiology
Cells, Cultured
Coronary Vessels / drug effects,  pathology*
DNA Fragmentation / drug effects
Endodeoxyribonucleases / genetics,  physiology*
Endothelium, Vascular / drug effects,  pathology*
Lipoproteins, LDL / pharmacology*
MAP Kinase Kinase 4 / antagonists & inhibitors,  physiology
Mice, Knockout
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors,  physiology
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors,  physiology
Models, Animal
Signal Transduction / physiology
Grant Support
Reg. No./Substance:
0/Lipoproteins, LDL; 0/carbamyl-LDL; EC Protein Kinase 1; EC Protein Kinase 3; EC Kinase Kinase 4; EC 3.1.-/Endodeoxyribonucleases; EC 3.1.21.-/endonuclease G

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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