Fiche publication
Date publication
septembre 2025
Journal
Pharmacological research
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BARRETO Guillermo
Tous les auteurs :
Cabrera-Fuentes HA, Ruiz-Meana M, Barreto G, Serebruany VL, Sánchez-Vega JT, Perez-Campos E, Kostin S, Böning A, González EEJ, Al-Suhaimi EA, Rodriguez-Montesinos J, Inserte J, Pedretti S, Yap J, Irei J, Sedding DG, Lecour S, Liehn EA, Garcia-Dorado D, Hausenloy DJ, Boisvert WA, Preissner KT
Lien Pubmed
Résumé
Myocardial ischemia/reperfusion (I/R) injury causes cardiomyocyte death and exacerbates inflammation. Emerging evidence implicates extracellular RNA (eRNA) and tumor necrosis factor-α (TNF-α) as key mediators. We hypothesize that eRNA released from ischemic cardiomyocytes amplifies I/R injury via TNF-α/TNF-receptor-1 (TNFR1) signaling, and that hydrolysis of eRNA by RNase1 can attenuate I/R injury by disrupting this pathway. Here, we investigated the mechanistic role of eRNA and its interplay with TNF-α signaling in cardiac I/R injury, and evaluated the therapeutic potential of RNase1 and cyclosporine-A (CsA). In ST-segment elevation myocardial infarction patients, plasma eRNA levels were significantly elevated 2h post-percutaneous coronary intervention, correlating positively with creatine kinase (CKmax). In murine I/R and hypoxia/reoxygenation models, eRNA released from stressed cardiomyocytes acted as a damage-associated molecular pattern, triggering TNF-α shedding via TACE/ADAM17 and activating TNFR1-mediated inflammation, mPTP opening, and cell death. Genetic deletion of TNF-α or TNFR1 abrogated eRNA-induced cytotoxicity, while TNFR2 deficiency exacerbated injury. Pharmacological inhibition of TACE with TAPI suppressed TNF-α release and preserved cell viability. RNase1 effectively degraded eRNA, blocking upstream pro-inflammatory signaling, whereas CsA preserved mitochondrial integrity by preventing mPTP opening. Notably, RNase1 and CsA showed synergistic protection in vivo when administered at reperfusion, significantly reducing myocardial infarct size. These findings identify eRNA as both a biomarker and pathogenic mediator of myocardial I/R injury, and support a dual-targeted strategy using RNase1 and CsA to interrupt the TNF-α/TNFR1-driven inflammatory and mitochondrial death pathways. Targeting both upstream inflammatory and downstream mitochondrial mechanisms represents a promising cardioprotective intervention for acute myocardial infarction.
Mots clés
Combination Therapy, Creatine Kinase (CK(max)), Cyclosporine-A (CsA), Extracellular ribonucleic acid (eRNA), STEMI, TAPI, TNF-α -converting-enzyme (TACE/ADAM17), acute myocardial infarction, cardioprotection, cell death mechanisms, inflammation, ischemia-reperfusion injury, ribonuclease-1 (RNase1), tumor necrosis factor-α (TNF-α)
Référence
Pharmacol Res. 2025 09 12;:107944
