Effect of Hypoxia on Macrophage MMP‐2 expression: Role of O2 availability in Determining Atherosclerotic Plaque Stability
Notice bibliographique
Résumé
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 .
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».