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Tetraploidy impairs human aortic endothelial cell (HAEC) function and is prevented by nicotinamide phosphoribosyltransferase (Nampt)

Senescent EC are found in atherosclerotic arteries and contribute to impaired vasodilation and inflammation. Polyploid EC are also found in atherosclerosis, but the consequences of this change are unclear. In HAEC, we found that tetraploidy precedes replicative senescence, is worsened during growth in high glucose, and is delayed by the NAD+ regenerating enzyme, Nampt. However, the impact of tetraploidy on EC function, independent of senescence, is unknown. Likewise, the effect of Nampt on EC genomic stability during replicative aging and glucose overload is unknown. We induced senescence‐independent tetraploidy by incubating HAEC with nocodazole for 48 h. After a 24 h recovery, these cells were 70% tetraploid, with no change in senescence‐associated β‐galactosidase activity. Growth rate and eNOS protein were decreased (‐38%, ‐23%) and ICAM‐1 protein was increased (19%). The effect of Nampt on tetraploidy associated with replicative senescence and glucose overload was assessed in HAEC expressing eGFP or eGFP‐Nampt and grown in basal (5 mM) or high (30 mM) glucose to the end of their lifespan. Nampt completely prevented aging‐ and glucose overload‐induced tetraploidy. We conclude that tetraploidy can independently impair HAEC function and that the emergence of tetraploidy during replicative aging and glucose overload can be prevented by enhancing NAD+ salvage. Research support: HSFO T5675, CIHR FRN11715.