Endonuclease G mediates endothelial cell death induced by carbamylated LDL

Research output: Contribution to journalArticle

Authors

  • Eugene O. Apostolov
  • Debarti Ray
  • Wilson M. Alobuia
  • Marina V. Mikhailova
  • Xiaoying Wang
  • Alexei G. Basnakian
  • Sudhir V. Shah

External Institution(s)

  • University of Arkansas for Medical Sciences
  • Department of Veterans Affairs

Details

Original languageEnglish (US)
Pages (from-to)H1997-H2004
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume300
Issue number6
StatusPublished - Jun 1 2011
Peer-reviewedYes

Abstract

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 mitogenactivated 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.

    Research areas

  • Atherosclerosis, Carbamylated low-density lipoprotein, Endonuclease G, Mitogen-activated protein kinase, Mitotic cell death

Citation formats

APA

Apostolov, E. O., Ray, D., Alobuia, W. M., Mikhailova, M. V., Wang, X., Basnakian, A. G., & Shah, S. V. (2011). Endonuclease G mediates endothelial cell death induced by carbamylated LDL. American Journal of Physiology - Heart and Circulatory Physiology, 300(6), H1997-H2004. https://doi.org/10.1152/ajpheart.01311.2010

Harvard

Apostolov, EO, Ray, D, Alobuia, WM, Mikhailova, MV, Wang, X, Basnakian, AG & Shah, SV 2011, 'Endonuclease G mediates endothelial cell death induced by carbamylated LDL', American Journal of Physiology - Heart and Circulatory Physiology, vol. 300, no. 6, pp. H1997-H2004. https://doi.org/10.1152/ajpheart.01311.2010