Abstract 16836: Pioglitazone Reduces Angiogenesis by Altering Mitochondrial Function and Reducing Hypoxia Inducible Factor-1 Activation
Bibliographic record
Abstract
Introduction: Thiazolidinediones (TZDs) used in type II diabetes are linked with adverse cardiovascular events by an unknown mechanism, including lower extremity revascularization. TZDs can affect mitochondria, which are oxygen sensors and therefore could regulate the angiogenic transcription factor hypoxia inducible factor 1 (HIF1) via mitochondrial derived α-ketoglutarate (αKG) and reactive oxygen species (mROS). We hypothesized that pioglitazone (PIO), a TZD, may impair angiogenesis through a mitochondrial-HIF1 dependent mechanism. Methods/Results: Human skeletal myocytes (hSMC) cultured at pO2 120 vs. 40 mmHg were treated with PIO (20 μ g/ml) for 24h. Compared to vehicle, PIO depolarized mitochondria, increased mROS and αKG in hypoxic hSMCs. PIO decreased HIF1 activity (nuclear translocation and decreased VEGF, a HIF1 regulated gene). In vitro, using a matrigel assay, PIO directly inhibited human microvascular endothelial cell (hMVEC) angiogenesis (tubule formation). To assess the paracrine effects and exclude the direct PIO effects on hMVEC, we used a Boyden chamber matrigel bioassay where hSMCs and hMVEC were separated by a cell impermeable membrane. Pre-treatment of hypoxic hSMCs with PIO had less angiogenesis than with vehicle. In vivo, neovascularization was assessed in diabetic (JCR:LP; n=20) and non-diabetic (SD; n= 22) rats. Hindlimb ischemia was induced, and the rats were treated with a clinically relevant PIO dose (10mg/kg/day) or placebo for 14 days. Ischemic hindlimb (gastrocnemius) perfusion was decreased in PIO treated animals (contrast enhanced ultrasound and Tc99m sestamibi micro CT-SPECT), which correlated with decreased angiogenesis (von Willebrand factor and lectin) in both diabetic and non-diabetic models. Conclusions: PIO alters mitochondrial function in hSMC, reducing HIF1 activation and inhibiting both paracrine/autocrine angiogenesis. PIO also impaired angiogenesis in diabetic and non-diabetic rats. Impairment of angiogenesis is undesirable in human diabetics with concomitant atherosclerotic vascular disease, and may be a mechanism for adverse effects of TZDs.
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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) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".