Loss of Mitochondrial Dynamics Proteins Mitofusin‐2 and Drp‐1 in Myocardial Ischemia‐Reperfusion Injury Is Prevented by Matrix Metalloproteinase‐2 Preferring Inhibitors
Notice bibliographique
Résumé
Objective Matrix metalloproteinase‐2 (MMP‐2) is a ubiquitous protease that cleaves several extracellular and intracellular proteins. MMP‐2 is activated intracellularly in response to enhanced oxidative stress resulting from myocardial ischemia/reperfusion (I/R) injury. Oxidative stress impairs mitochondrial function which is regulated by different proteins including mitofusin‐2 (Mfn‐2) and dynamin‐related protein‐1 (Drp‐1) which control mitochondrial dynamics involving fusion and fission, respectively. As both proteins are localized at the mitochondrial outer membrane and MMP‐2 is localized at the mitochondrial‐endoplasmic reticulum associated membrane we hypothesized that MMP‐2 may proteolyze Mfn‐2 and Drp‐1. We therefore investigated whether inhibition of MMP‐2 could protect against the loss of mitochondrial dynamics proteins during I/R injury. Methods Hearts isolated from 3 month old C57BL/6J mice were perfused according to Langendorff at constant pressure and subjected to I/R injury (30 min ischemia and 40 min reperfusion) in absence or presence of MMP‐2 preferring inhibitors ARP‐100 (10 µM) or ONO‐4817 (50 µM) or their vehicle (n=5 hearts per group). Effects on mechanical function were recorded. At the end of reperfusion, the hearts were homogenized and subcellular fractions were prepared. The degradation of troponin I (TnI), an intracellular MMP‐2 target, was measured in the cytosolic fraction as a marker of MMP‐2 activity. Levels of Mfn‐2 and Drp‐1 in the mitochondrial fraction were also measured using western blot. In silico analysis of potential MMP‐2 cleavage sites was performed using Procleave. Results ARP‐100 or ONO‐4817 significantly increased left ventricular developed pressure compared to vehicle‐treated I/R hearts (% of pre‐ischemic baseline value at R40: IR+vehicle 25.5±3.2, IR+ARP 50.1±3.2, IR+ONO 57.3±1.6%, p<0.05). Similarly, both inhibitors significantly improved the rates of contraction and relaxation (+/‐dP/dt). TnI loss was increased in I/R hearts as shown by a significant reduction in TnI (~30 kDa) and the appearance of an ~22 kDa band. ARP‐100 or ONO‐4817 attenuated TnI loss, indicating MMP‐2 activation. Levels of Mfn‐2 and Drp‐1 in the mitochondrial fraction were significantly reduced in the I/R group and ARP‐100 or ONO‐4817 attenuated this reduction (p<0.05). Similar results were obtained using a different Mfn‐2 antibody that binds to its C‐terminus. In silico analysis of both mouse Mfn‐2 and Drp‐1 sequences showed several potential sites that could be targeted by MMP‐2. Conclusions During myocardial I/R injury, MMP‐2 may affect mitochondrial dynamics by proteolysis of Mfn‐2 and Drp‐1. Inhibition of MMP‐2 activity could protect against cardiac contractile dysfunction in part by preserving these proteins affecting mitochondrial fusion and fission.
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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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 | 0,001 |
| 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 ».