Abstract 5808: Endothelial Cell Polyploidization Induces an Atherogenic Phenotype and is Prevented by Activating the Nampt-SIRT1 Axis
Bibliographic record
Abstract
Polyploid endothelial cells (ECs) are found in aged and atherosclerotic arteries. However, whether increased chromosome content has an impact on EC function is unknown. To interrogate the process by which ECs become polyploid we tracked cellular DNA content by flow cytometry in human aortic ECs as they replicated over 130 days. Strikingly, we observed that almost all ECs (99%) became tetraploid as they approached replicative senescence. Furthermore, the accumulation of tetraploid ECs was accelerated when cells were concurrently subjected to the oxidative stress of high glucose. To determine the impact of tetraploidy on EC function, independent of replicative senescence, we induced tetraploidy using the spindle poison, nocodazole. After a 24 h recovery, 70% of the EC population was tetraploid with no change in senescence-associated β -galactosidase activity. High density microarray expression analyses of tetraploid ECs revealed an atherogenic 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 ). Interestingly, aging-induced polyploidization was prevented by modest (1.6-fold) overexpression of the NAD + -regenerating enzyme, nicotinamide phosphoribosyltransferase (Nampt). The protection from polyploidization conferred by Nampt was not associated with enhanced PARP-1 or SIRT2 activity but with increased SIRT1 activity, which reduced cellular ROS and the associated oxidative stress stimulus for polyploidization. We conclude that human aortic ECs are prone to chromosome duplication that, in and of itself, can induce an atherogenic EC phenotype. Moreover, the emergence of tetraploid ECs can be prevented by optimizing the Nampt-SIRT1 axis. Strategies to maintain EC NAD + levels may represent a novel approach to mitigate the potentially deleterious accumulation of polyploid ECs associated with vascular disease.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".