<i>MicroRNA-26b−/−</i> augments atherosclerosis, while mimic-loaded nanoparticles reduce atherogenesis
Bibliographic record
Abstract
AIMS: Increasing evidence has shown that microRNAs (miRs) play a fundamental role in atherosclerosis, but the exact role of various miRs remains elusive. Preliminary data showed that, with a five-fold increase, miR-26b was highly expressed in human atherosclerotic plaques compared to healthy vessels. Therefore, we aimed to determine its cell-specific effects on atherosclerosis development and its therapeutic potential. METHODS AND RESULTS: We examined the role of miR-26b in atherosclerosis by using whole-body Apoe-/-Mir26b-/- and myeloid cell-specific miR-26b-deficient (LysM-Cre) mice on a Western-type diet (WTD). Atherosclerotic plaque size and phenotype, as well as the phenotype and function of bone marrow-derived macrophages (BMDMs) from Apoe-/-Mir26b-/- mice, were investigated. Lipid nanoparticles (LNPs) served as vehicles for miR-26b mimics to restore miR-26b levels in miR-26b-deficient BMDMs in vitro and in mice in vivo. Apoe-/-Mir26b-/- mice have a striking 2.8-fold increase in atherosclerotic lesion size in the aortic arch after 12-week WTD, compared to control Apoe-/-, while lesions in the aortic root were unaffected. Consistent with a more advanced plaque phenotype, collagen, smooth muscle cell, and necrotic core content were all significantly increased in plaques from Apoe-/-Mir26b-/- mice, whilst the relative macrophage content was significantly reduced. This phenotype could also be observed in Apoe-/-Mir26b-/- mice after 4-week WTD. Intriguingly, relative plaque size in the arches of Apoe-/-LysmCre+Mir26bfl/fl mice was increased by 2.5-fold, suggesting a role for myeloid-specific miR-26b in atherosclerosis development. Further highlighting its myeloid-specific effects, Apoe-/-Mir26b-/- BMDMs showed an increase in pro-inflammatory cytokine secretion, which could be rescued by LNPs containing miR-26b mimics. MiR-26b pull-down analysis revealed AnnexinA2 as one of the novel targets playing a key role in these effects, which could be validated in BMDMs in vitro. Furthermore, in vivo treatment of Apoe-/-Mir26b-/- mice as well as ex vivo treatment of human plaques with miR-26b-mimic-loaded LNPs demonstrated their therapeutic potential and human relevance, respectively. CONCLUSION: Overall, our results clearly demonstrate an atheroprotective role of miR-26b by attenuating lesion formation, mainly by suppressing inflammation and stimulating collagen breakdown. Furthermore, the therapeutic potential of miR-26b mimic-loaded LNPs could be proven, opening up new avenues for miRNA-based treatment options in the future.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".