Effect of Hypoxia on Macrophage MMP‐2 expression: Role of O2 availability in Determining Atherosclerotic Plaque Stability
Bibliographic record
Abstract
Atherosclerotic plaque accumulation at the carotid artery bifurcation is a leading cause of stroke. Stroke symptoms occur when the atherosclerotic plaque ruptures and forms thrombus, causing material to embolize into the cerebral circulation. For years, there has been speculation that increased expression of matrix metalloproteinases (MMPs) within atherosclerotic plaques may be responsible to plaque rupture, however, which MMPs are responsible for increase plaque instability and the potential mechanism(s) that induces this change remain to be elucidated. One proposed mechanism is changes in [O2] in the plaque environment. In the present study, we examined the relative expression of MMPs (MMPs‐2, ‐15 and‐24) in carotid artery plaques (n=36; 23 symptomatic; a history of TIA/stroke within last 4 months and 13 asymptomatic; a history of TIA/stroke >4 months) and blood (n=25; 17 symptomatic and 8 asymptomatic) from patients undergoing carotid endarterectomy procedures (plaque removal). Methods Relative changes in MMPs levels were measured in both plaques and peripheral blood mononuclear cell (PBMCs) by real‐time quantitative PCR (QPCR). Western blot analysis was utilized to determine changes in MMP‐2 levels in asymptomatic versus symptomatic plaques and PBMCs. Cellular localisation of MMP‐2 in atherosclerotic carotid plaques were examined by immunohistochemistry (IHC). To further investigate the mechanism of MMP‐2 production within atherosclerotic plaques, in‐vitro differentiated THP‐1 macrophage cells were exposed to either hypoxic or normoxic conditions and both RNA and protein levels of hypoxia induced factor‐ 1 alpha (HIF‐1α) and MMP‐2 were analyzed at different time points. Finally, effects of reoxygenation (normoxia) in hypoxic THP‐1 cells were determined. Results Our main findings were (i) Symptomatic patients had significantly lower expression levels of MMP‐2 mRNA in plaques compared to asymptomatic plaques, however there was a significant increase in MMP2 RNA in circulating monocytes of symptomatic patients (ii) Protein levels of MMP‐2 were found markedly up‐regulated in both plaques and blood of symptomatic patients. iii) IHC showed that MMP‐2 were co‐localized to macrophages iv) in‐vitro studies suggest that the hypoxic conditions markedly increased MMP‐2 production in a concentration dependent manner, and v) The reoxygenation to differentiated THP‐1 cells after 24 hours of hypoxia resulted in a sustained expression of MMP‐2, as determined by Western blot assays. These results suggest that increased level of MMP‐2 within atherosclerotic carotid plaques could contribute to atherosclerosis progression, and plaque rupture. Conclusion It appears that exposure of macrophages to hypoxia induces MMP2 expression and this, in turn, leads to inflammatory changes and matrix degradation within the atherosclerotic lesions. Thus, MMP‐2 could be a potential therapeutic target not only for plaque stabilization but also as a biomarker for vulnerable atherosclerotic plaques in blood. Support or Funding Information SHRF This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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) | 0.001 | 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".