RESUMEN
BACKGROUND: We investigated whether postinfarct treatment with oxytocin (OT) improves left ventricular (LV) function and remodeling via cardiac repair of myocardial ischemia-reperfusion injury. METHODS AND RESULTS: Experiments were performed with 30 minutes of coronary occlusion and 2 or 14 days of reperfusion rabbit model of myocardial infarction. LV function and remodeling were significantly improved in the OT group. The infarct size was significantly reduced in the OT group. The number of CD31-positive microvessels was increased significantly in the OT group. There were no Ki67-positive myocytes in either group. The expression of the OT receptor, phosphorylated (p)-Akt protein kinase, p-extracellular signal-regulated protein kinase, p-enodthelial NO synthase, p-signal transducer and activator of transcription 3, vascular endothelial growth factor, B-cell lymphoma 2, and matrix metalloproteinase-1 (MMP-1) were markedly increased in the OT group days 2 and 14 post myocardial infarction. CONCLUSIONS: Postinfarct treatment with OT reduces myocardial infarct size and improves LV function and remodeling by activating OT receptors and prosurvival signals and by exerting antifibrotic and angiogenic effects through activation of MMP-1, endothelial NO synthase, and vascular endothelial growth factor. These findings provide new insight into therapeutic strategies for ischemic heart disease.
Asunto(s)
Infarto del Miocardio/tratamiento farmacológico , Neovascularización Fisiológica/efectos de los fármacos , Oxitocina/uso terapéutico , Transducción de Señal/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Ciclina D1/metabolismo , Modelos Animales de Enfermedad , Ecocardiografía , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Corazón/efectos de los fármacos , Corazón/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Masculino , Metaloproteinasa 1 de la Matriz/metabolismo , Microvasos/anatomía & histología , Microvasos/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Oxitocina/farmacología , Fosforilación/efectos de los fármacos , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Conejos , Receptores de Oxitocina/metabolismo , Factor de Transcripción STAT3/metabolismo , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular Izquierda/fisiología , Remodelación Ventricular/fisiologíaRESUMEN
AIMS: We investigated the effect of an erythropoietin (EPO)-gelatin hydrogel drug delivery system (DDS) applied to the heart on myocardial infarct (MI) size, left ventricular (LV) remodelling and function. METHODS AND RESULTS: Experiments were performed in a rabbit model of MI. The infarct size was reduced, and LV remodelling and function were improved 14 days and 2 months after MI but not at 2 days after MI in the EPO-DDS group. The number of cluster of differentiation 31(CD31)-positive microvessels and the expression of erythropoietin receptor (EPO-R), phosphorylated-Akt (p-Akt), phosphorylated glycogen synthase kinase 3beta (p-GSK-3beta), phosphorylated extracellular signal-regulated protein kinase (p-ERK), phosphorylated signal transducer and activator of transcription 3 (p-Stat3), vascular endothelial growth factor (VEGF), and matrix metalloproteinase-1 (MMP-1) were significantly increased in the myocardium of the EPO-DDS group. CONCLUSION: Post-MI treatment with an EPO-DDS improves LV remodelling and function by activating prosurvival signalling, antifibrosis, and angiogenesis without causing any side effect.
Asunto(s)
Fármacos Cardiovasculares/farmacología , Eritropoyetina/farmacología , Gelatina/química , Hidrogeles , Infarto del Miocardio/tratamiento farmacológico , Miocardio/patología , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Animales , Western Blotting , Fármacos Cardiovasculares/administración & dosificación , Fármacos Cardiovasculares/química , Supervivencia Celular/efectos de los fármacos , Química Farmacéutica , Modelos Animales de Enfermedad , Formas de Dosificación , Portadores de Fármacos , Eritropoyetina/administración & dosificación , Eritropoyetina/química , Fibrosis , Humanos , Inmunohistoquímica , Inyecciones Subcutáneas , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/enzimología , Neovascularización Fisiológica/efectos de los fármacos , Conejos , Proteínas Recombinantes , Transducción de Señal/efectos de los fármacos , Factores de TiempoRESUMEN
BACKGROUND: Statins reportedly protect against myocardial infarction, but the precise mechanism is unclear. METHODS AND RESULTS: Rabbits underwent 30 min of coronary occlusion followed by 48 h of reperfusion. Pravastatin (1 or 5 mg/kg) or saline was intravenously administered 10 min before ischemia. Pravastatin (5 mg/kg) was also administered 10 min before reperfusion. N(omega)-nitro-L-arginine methylester (L-NAME, 10 mg/kg), chelerythrine (5 mg/kg) or 5-hydroxydecanoic acid sodium salt (5-HD, 5 mg/kg) was intravenously administered 10 min before pravastatin injection. The infarct size was determined. The myocardial interstitial levels of 2,5-dihydroxybenzoic acid (DHBA) and nitrogen oxide (NOx), and the intensity of myocardial dihydroethidium staining were measured. Pre-ischemic treatment with pravastatin reduced the infarct size (34+/-5% and 24+/-4%, 1 and 5 mg/kg, respectively), but not pre-reperfusion treatment (42.1+/-3.7%), compared with the control (45+/-3%). This effect was blocked by L-NAME (42.6+/-4%), chelerythrine (50.9+/-3%) and 5-HD (52.7+/-2%). Pre-ischemic treatment with pravastatin increased myocardial NOx levels, and attenuated both the 2,5-DHBA level and the intensity of dihydroethidium staining during reperfusion. Chelerythrine abolished the increase in NOx levels by pravastatin. CONCLUSION: Pre-ischemic treatment with pravastatin reduces the myocardial infarct size via protein kinase C-dependent nitric oxide production, decreasing hydroxyl radicals and superoxide, and opening the mitochondrial adenosine triphosphate-sensitive potassium channels.