Mevalonate Depletion Impairs Survival of Primary Human Mesenchymal Stem Cells through Down Regulation of NF-κB
Bibliographic record
Abstract
Background: Circulating progenitor cells of bone marrow origin have been implicated to neointima formation and constructive remodeling in vascular injury and transplant cardiac allograft vasculopathy (CAV). Hydroxymethylglutaryl-Coenzyme A (HMG-CoA) reductase inhibitors (“statins”) have been shown to slow the progression of CAV and improve patient survival, which was presumed to be as a result of altered lipid metabolism. Statins also exhibit other positive pleiotropic properties such as modulation of inflammatory response via a mechanism independent of cholesterol reduction. We examined the effect of HMG-CoA reductase inhibition with three statins (atorvastatin, simvastatin and pravastatin) on the viability of primary human bone marrow derived mesenchymal stem cells (MSC) in culture. Methods: The protocol received IRB approval. MSC were isolated from bone marrow collected from the sternum of patients undergoing open heart surgery and were cultured in standard conditions. Cells were treated with atorvastatin, simvastatin or pravastatin 0.1, 1.0 or 10 μM ± mevalonate for 48 or 96 hours. Optical MTT assay was performed to assess cell viability. Viability was also assessed based on physical and biochemical properties of the cell using live-dead assay. NF-κB p65 expression was assessed by western blot. Rescue of NF- κB pathway function was achieved through overexpression of Ikk-β with an adenoviral vector. Results: Treatment of MSC with 0.1, 1 or 10 μM atorvastatin or simvastatin resulted in progressively reduced cell viability up to 50% in a time and dose dependent manner which was associated with a corresponding progressive decline in NF-κB p65 expression. Viability could be rescued by coincubation with mevalonate or pretreatment with Ikk-β adenoviral vector. Treatment with pravastatin did not show any effect on cell viability or NF-κB p65 expression. Conclusions: Mevalonate depletion through HMG-CoA reductase inhibition impairs the viability of primary human MSC in culture through NF-κB p65 depletion. This additional pleiotropic effect of statins may provide an insight into the benefits of this therapy independent of its effect on lipid metabolism. The lack of effect on MSC viability by pravastatin could be due to the hydrophilic nature of the molecule.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".