Hydrogen Sulfide (H2S) Metabolism, Iron Overload, and Apoptosis–Autophagy Equilibrium in Vascular Smooth Muscle Cells
Bibliographic record
Abstract
Iron overload contributes to proliferative vascular diseases, yet its interplay with hydrogen sulfide (H2S) in vascular smooth muscle cell (VSMC) proliferation remains poorly understood. This study elucidates H2S’s role in mitigating iron-overload-induced oxidative stress and cellular damage. Using aortic VSMCs from wildtype (WT) and cystathionine γ-lyase-knockout (CSE-KO) mice treated with ferric ammonium citrate (FAC) at concentrations equivalent to serum levels of iron and citrate, we demonstrate that FAC triggers the integrated stress response (ISR) in WT cells, upregulating CSE to enhance H2S production. The ISR mediator ATF4 activates caspases but simultaneously induces CSE, which inhibits caspase activity and promotes autophagy via AMPK signaling. In CSE-KO cells, iron overload leads to diminished Ferritin upregulation, unchecked Caspase activation, and impaired autophagy compared to WT cells. Exogenous H2S restored iron homeostasis by enhancing Ferritin expression, activating NRF2 antioxidant pathways, and restoring apoptosis–autophagy equilibrium in both WT and KO cells. These findings establish H2S as a critical regulator of iron-induced VSMC dysfunction, highlighting its therapeutic potential in managing vascular pathologies linked to iron dysregulation.
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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 | 0.000 | 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) | 0.000 | 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".