Glucose‐Derived Extracellular Endothelial Microvesicles Induce a Pathologic Endothelial Phenotype
Bibliographic record
Abstract
Hyperglycemia is associated with an increased risk and prevalence of cardiovascular disease (CVD), due in large part to the adverse effects of glucose on endothelial cells. Indeed, hyperglycemic conditions can damage endothelial cells, in turn, impairing endothelial vasomotor and fibrinolytic function, exacerbating inflammatory and oxidative processes and propagating a proapoptotic phenotype. In addition to these primary effects, glucose also stimulates the release of extracellular microvesicles from endothelial cells. Extracellular endothelial microvesicles (EMVs) have emerged as causative agents in vascular pathology owing to their numerical increase in disease states, including diabetes, and cellular effects. The effects of glucose‐derived EMVs on endothelial cell function is not clear. The experimental aim of this study was to determine, in vitro, the effect of glucose‐derived EMVs on endothelial cell inflammation, oxidative stress, and nitric oxide (NO) production. Human umbilical vein endothelial cells (HUVECs) were cultured (3 rd passage) and incubated with RPMI 1640 media containing 25mM D‐glucose (concentration representing a diabetic glycemic state) or 5mM D‐glucose (control, normoglycemic condition) for 48 h to generate EMVs. EMVs (CD144‐PE) were counted and isolated by flow cytometry. Thereafter, HUVECs (2 x10 6 cells/condition) were treated with EMVs (2:1 EMV:cell ratio) generated from either the high (hgEMV) or normal (ngEMV) glucose condition for 24 h. EMV release was markedly higher (~280%; P<0.05) in cells treated with high vs normal glucose (134.7±15.6 vs. 35.4±3.2 EMV/µL). hgEMVs induced significantly higher release of cytokines IL‐6 (26.6±1.5 vs. 20.7±1.6 pg/mL) and IL‐8 (40.5±4.1 vs. 26.4±2.9 pg/mL); in addition, expression of active NF‐κB p65 (Ser‐536) was higher in the hgEMV treated cells (7.6±1.0 vs. 3.4±0.5 AU; P<0.05). Intracellular ROS production was higher(~26%) in the cells treated with hgEMVs (72.5±3.4 %) vs ngEMVs (57.7±1.8%). Active endothelial nitric oxide synthase (p‐eNOS Ser1177) (10.6±1.6 vs 31.7±5.2 AU) and NO production (7.7±0.2 vs. 11.6±1.1 umol/L) were both significantly lower (~30% and 20%, respectively) in hgEMV treated cells. Blocking NF‐kB activation using IKK‐2 inhibitor IV abolished the increase in IL‐6 and IL‐8 release in response to hgEMVs, verifying hgEMV induced NF‐kB‐mediated inflammation. Inhibiting endocytosis prevented the proinflammatory, pro‐oxidative and anti‐NO effects of hgEMVs; whereas, RNase‐inactivation (RNase A/T1) of hgEMVs eliminated their negative effects on endothelial proteins regulating inflammation, oxidative stress and NO production. These data demonstrate that: 1)high glucose‐derived EMVs induce a proinflammatory, pro‐oxidative, proatherogenic endothelial phenotype; and 2) EMV internalization and intracellular delivery of RNA regulatory cargo are central mechanisms underlying these deleterious cellular effects.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".