The interaction among hydrogen sulfide, estrogen and insulin-like growth factor-1 in vascular smooth muscle cells
Bibliographic record
Abstract
The proliferation of vascular smooth muscle cells (SMCs) is regulated by an array of endogenous substances, including estrogen, insulin-like growth factor-1 (IGF-1), and hydrogen sulfide (H2S). Estrogen inhibits SMC proliferation via the activation of estrogen receptor-α (ER- α), but it stimulates the same in the absence of endogenous H2S. IGF-1, via its receptor (IGF- 1R), stimulates SMC proliferation and migration. ER-α and IGF-1R can form hybrid dimer with both ER and IGF-1 as the binding ligands. Furthermore, H2S produced by cystathionine-gamma lyase (CSE) inhibits SMC proliferation. It appears that the interaction and integration of the vascular effects of estrogen, IGF-1, and H2S determine the outcome of the proliferation of SMCs. In this thesis study, we found that plasma estrogen levels were significantly lower in female CSE knockout (KO) mice than in female wide-type (WT) mice. Estrogen treatment of atherogenic diet-fed mice attenuated hypercholesterolemia, oxidative stress, intracellular adhesion molecule-1 and NF-κB expression and increased H2S production in WT mice but not in CSE- KO mice. Not only estrogen and H2S affects each other’s production and function, H2S also interacts with IGF-1 to inhibit the stimulatory effect of IGF-1 on SMCs proliferation. This inhibitory effect of H2S was abolished by blocking IGF-1/IGF-1R signaling pathway. On the other hand, estrogen downregulated the protein expressions of IGF-1 and IGF-1R in mouse aortic tissues or aortic SMCs. Deficiency of IGF-1R expression or lower IGF-1R activity abolished the stimulatory effect of estrogen on the proliferation of CSE-KO SMCs. ER-α and IGF-1R were co-located on cell membrane and co-immunoprecipitated. The binding of estrogen to IGF-1R/ER-α hybrid catalyzed the stimulatory effect on SMC proliferation. Finally, H2S induced the S-sulfhydration of IGF-1R, but not ER-α, in mouse SMCs, which lead to the decreased formation of IGF-1R/ER-α hybrid. This decrease inhibited the phosphorylation of IGF-1R, and attenuated estrogen-induced SMC proliferation. It is concluded that the antiatherosclerotic effect of estrogen is mediated by CSEgenerated H2S. The absence of H2S favors the interaction of estrogen with IGF-1R/ER-α hybrid to stimulate SMC proliferation whereas the presence of H2S favors the interaction of estrogen with ER-α to inhibit SMC proliferation. Our studies demonstrate that H2S reverses the proproliferative effect of estrogen on SMCs and unmasks the dominative anti-atherosclerotic effect of estrogen. The appreciation of the critical role of H2S in the cardiovascular effects of estrogen and IGF-1 will help better understand the regulation of the complex vascular effects of estrogen and sex-related cardiovascular diseases
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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) | 0.000 | 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 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".