RESUMEN
PURPOSE: Protecting the heart from ischaemia-reperfusion (IR) injury is a major goal in patients presenting with an acute myocardial infarction. Pyroptosis is a novel form of cell death in which caspase 1 is activated and cleaves interleukin 1ß. VX-785 is a highly selective, prodrug caspase 1 inhibitor that is also clinically available. It has been shown to be protective against acute IR in vivo rat model, and therefore might be a promising possibility for future cardioprotective therapy. However, it is not known whether protection by VX-765 involves the reperfusion injury salvage kinase (RISK) pathway. We therefore investigated whether VX-765 protects the isolated, perfused rat heart via the PI3K/Akt pathway and whether protection was additive with ischaemic preconditioning (IPC). METHODS: Langendorff-perfused rat hearts were subject to ischaemia and reperfusion injury in the presence of 30 µM VX-765, with precedent IPC, or the combination of VX-765 and IPC. RESULTS: VX-765 reduced infarct size (28 vs 48% control; P < 0.05) to a similar extent as IPC (30%; P < 0.05). The PI3 kinase inhibitor, wortmannin, abolished the protective effect of VX-765. Importantly in the model used, we were unable to show additive protection with VX-765 + IPC. CONCLUSIONS: The caspase 1 inhibitor, VX-765, was able to reduce myocardial infarction in a model of IR injury. However, the addition of IPC did not demonstrate any further protection.
Asunto(s)
Caspasa 1/metabolismo , Inhibidores de Caspasas/farmacología , Dipéptidos/farmacología , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/enzimología , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , para-Aminobenzoatos/farmacología , Animales , Citoprotección , Modelos Animales de Enfermedad , Preparación de Corazón Aislado , Masculino , Infarto del Miocardio/enzimología , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/enzimología , Daño por Reperfusión Miocárdica/patología , Miocardio/patología , Piroptosis/efectos de los fármacos , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
The alpha2-adrenergic receptor agonist Dexmedetomidine (Dex) is a sedative medication used by anesthesiologists. Dex protects the heart against ischemia-reperfusion (IR) and can also act as a preconditioning mimetic. The mechanisms involved in Dex-dependent cardiac preconditioning, and whether this action occurs directly or indirectly on cardiomyocytes, still remain unclear. The endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling pathway and endothelial cells are known to play key roles in cardioprotection against IR injury. Therefore, the aims of this work were to evaluate whether the eNOS/NO pathway mediates the pharmacological cardiac effect of Dex, and whether endothelial cells are required in this cardioprotective action. Isolated adult rat hearts were treated with Dex (10nM) for 25min and the dimerization of eNOS and production of NO were measured. Hearts were then subjected to global IR (30/120min) and the role of the eNOS/NO pathway was evaluated. Dex promoted the activation of eNOS and production of NO. Dex reduced the infarct size and improved the left ventricle function recovery, but this effect was reversed when Dex was co-administered with inhibitors of the eNOS/NO/PKG pathway. In addition, Dex was unable to reduce cell death in isolated adult rat cardiomyocytes subjected to simulated IR. Cardiomyocyte death was attenuated by co-culturing them with endothelial cells pre-treated with Dex. In summary, our results show that Dex triggers cardiac protection by activating the eNOS/NO signaling pathway. This pharmacological effect of Dex requires its interaction with the endothelium.