Abstract 79: Examining the Role of Endoplasmic Reticulum Stress Induced Glycogen Synthase Kinase-3a/ß in Accelerated Atherosclerosis
Bibliographic record
Abstract
Introduction Cardiovascular disease accounts for a third of all deaths in the western world, however our understanding of the molecular mechanisms of atherosclerosis development is incomplete. Our previous findings have suggested that endoplasmic reticulum (ER) stress plays a causative role in atherogenesis. The objective of this study is to investigate how ER stress promotes atherosclerosis with a specific focus on ER stress-induced Glycogen Synthase Kinase (GSK)-3α and β. Methods and Results Established mouse models of accelerated atherosclerosis including hyperglycemia, hyperhomocysteinemia and relative dyslipidemia in female ApoE-/- mice were examined. A subset of mice from each group was supplemented with valproate (625 mg/kg), a compound with GSK3α/β inhibitory properties. Hyperglycemia, hyperhomocysteinemia and high fat diet elevated ER stress levels in multiple tissues, enhanced GSK3β activity, increased atherosclerotic plaque size, and induced hepatic steatosis. Valproate-supplementation significantly attenuated GSK3 activation, aortic plaque development and hepatic steatosis without altering ER stress levels. ER stress and valproate appears to modulate GSK3 activity by altering its phosphorylation status. To examine the mechanism linking ER stress to the activation of pro-atherogenic pathways, cultured THP1-derived macrophages were treated with the ER stress inducing agents, glucosamine (5mM), thapsigargin (1.5μM) or palmitate (800μM). GSK3α/β activity was inhibited with the specific inhibitor CT99021 (4μM). In macrophages, ER stress upregulated the mRNA expression of genes controlling lipid biosynthesis while GSK3α/β inhibition attenuated lipid synthesis. The expression of downstream targets of the PERK ER stress signaling pathway, CHOP and ATF4, were downregulated by GSK3α/β inhibition. Further, PERK-/- mouse embryonic fibroblasts (MEFs) had significantly attenuated lipid accumulation while expression of constitutively active GSK3β-S9A restored the ability of PERK deficient cells to accumulate lipids. Conclusions These findings support the a common pathway that links cardiovascular risk factors to the activationof pro-atherogenic pathways by a mechanism involving ER stress-induced GSK3α/β.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".