Microparticles Induce Cell Cycle Arrest Through Redox‐Sensitive Processes in Endothelial Cells: Implications in Vascular Senescence
Bibliographic record
Abstract
BACKGROUND: Chronic disease accelerates endothelial dysfunction in aging, a process associated with cell senescence. However, the mechanisms underlying this process are unclear. We examined whether endothelial cell (EC)-derived microparticles (MPs) facilitate EC senescence and questioned the role of reactive oxygen species in this process. METHODS AND RESULTS: Senescence was induced by sequential passaging of primary mouse ECs. Cells retained phenotypic characteristics of ECs from passage 4 through passage 21. Passage 21 ECs exhibited features of senescence, including increased staining of senescence-associated β-galactosidase (SA-βgal), a greater percentage of cells in G(1)/G(0) phase of the cell cycle, and increased phosphorylation of p66(Shc) (P<0.05). Microparticle formation from passage 21 ECs was increased versus passage 4 ECs (∼2.2-fold increase versus passage 4, P<0.05), and the Rho kinase inhibitor fasudil blocked this increase. Exposure of passage 4 ECs to MPs shifted cells from a proliferating to a nonproliferating phenotype, as indicated by cell cycle analysis and increased senescence-associated β-galactosidase staining. MPs increased EC generation of O(2) (•-) (∼2.7-fold) and H(2)O(2) (∼2.6-fold), effects blocked by apocynin (nicotinamide adenine dinucleotide phosphate oxidase inhibitor) and rotenone (mitochondrial oxidase inhibitor) but not by allopurinol (xanthine oxidase inhibitor). MPs increased expression of cell cycle proteins p 21 cip1 and p16ink4a and stimulated phosphorylation of p66(Shc) in ECs (P<0.05 versus untreated ECs). Pretreatment with the reactive oxygen species scavenger sodium 4,5-dihydroxybenzene-1,3-disulfonate (tiron) abrogated the prosenescent effects of MPs. CONCLUSIONS: MPs promote EC senescence through nicotinamide adenine dinucleotide phosphate oxidase- and mitochondrial-derived reactive oxygen species. Such redox-sensitive processes may be important in vascular dysfunction in aging. (J Am Heart Assoc. 2012;1:e001842 doi: 10.1161/JAHA.112.001842.).
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".