Polyploidy impairs human aortic endothelial cell function and is prevented by nicotinamide phosphoribosyltransferase.
Polyploid endothelial cells are found in aged and atherosclerotic arteries. However, whether increased chromosome content has an impact on endothelial cell function is unknown. We show here that human aortic endothelial cells become tetraploid as they approach replicative senescence. Furthermore, accumulation of tetraploid endothelial cells was accelerated during growth in high glucose. Interestingly, induction of polyploidy was completely prevented by modest overexpression of the NAD+ regenerating enzyme, nicotinamide phosphoribosyltransferase (Nampt). To determine the impact of polyploidy on endothelial cell function, independent of replicative senescence, we induced tetraploidy using the spindle poison, nocodazole. Global gene expression analyses of tetraploid endothelial cells revealed a dysfunctional phenotype characterized by a cell cycle arrest profile (decreased CCNE2/A2, RBL1, BUB1B; increased CDKN1A) and increased expression of genes involved in inflammation (IL32, TNFRSF21/10C, PTGS1) and extracellular matrix remodeling (COL5A1, FN1, MMP10/14). The protection from polyploidy conferred by Nampt was not associated with enhanced poly(ADP-ribose) polymerase-1 or sirtuin (SIRT) 2 activity, but with increased SIRT1 activity, which reduced cellular reactive oxygen species and the associated oxidative stress stimulus for the induction of polyploidy. We conclude that human aortic endothelial cells are prone to chromosome duplication that, in and of itself, can induce characteristics of endothelial dysfunction. Moreover, the emergence of polyploid endothelial cells during replicative aging and glucose overload can be prevented by optimizing the Nampt-SIRT1 axis.
London Health Sciences Centre, 339 Windermere Rd., London, Ontario, Canada N6A 5A5.
Nica M
NM
Borradaile
J Geoffrey
JG
Pickering
D000375:Aging; D001011:Aorta; D050197:Atherosclerosis / Q000235:genetics / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005109:Extracellular Matrix / Q000235:genetics; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000235:genetics; D054409:Nicotinamide Phosphoribosyltransferase / Q000494:pharmacology*; D015739:Nocodazole / Q000494:pharmacology; D011123:Polyploidy
D016207:Cytokines; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D005947:Glucose; D015739:Nocodazole