Efeitos do pré-tratamento com o fator estimulante de colônia de granulócitos (G-CSF) sobre o desenvolvimento do infarto do miocárdio em ratos

• Autor(a) principal: Baldo, Marcelo Perim
• Data de Publicação: 2008
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Repositório Institucional da Universidade Federal do Espírito Santo (riUfes)
• Texto Completo: http://repositorio.ufes.br/handle/10/7914
• topic: Myocardial infarction; Apoptosis; Ventricular arrhythmias; Remodeling; Mortality; G-CSF; Infarto do miocárdio; Apoptose; Arritmias ventriculares; Remodelamento; Mortalidade; Fisiologia; 612

Background. The granulocyte colony-stimulating factor (G-CSF) mobilizes bone marrow stem cells and in the case of a cardiac pathophysiological event, such as acute myocardial infarction, they would repair the injured myocardium. Improvement in cardiac function, decrease in infarction size and mortality were related to G-CSF treatment. With the knowledge’s evolution in this area, a direct effect on myocardium was evidenced as responsible to some beneficial effects, and that cardiac regeneration had a small contribution to this effects. Aims. In agreement with this data, we propose to evaluate the effects of pretreatment with G-CSF on acute phase of myocardial infarction, and its impacts in the cardiac remodeling process and to heart failure evolution. Methods. Male Wistar rats (180-240g) were randomized to receive G-CSF (50µg/kg, sc) or vehicle, at 7, 3 and 1 days before surgery. Myocardial infarction was induced by permanent occlusion of left descending coronary artery and the infarction size was measured through tripheniltetrazolium chloride (24 hours) or by infarction scar area (15 days). A group of animals were submitted to false-surgery and used as control (Sham). Protein expression was made immediately before myocardial infarction induction by Western blot, in a sample of the left ventricle. To evaluate the postinfarction ventricular arrhythmias, the animals were anesthetized with pentobarbital (60mg/kg, ip) and the electrocardiogram was monitored by 30 minutes after occlusion. The number of premature ventricular complex, incidence and duration of ventricular tachycardia (VT) and the incidence of ventricular fibrillation (VF) were computed. Hemodynamic measurements were performed 15 days after myocardial infarction through ventricular catheterization under ketamine (70mg/kg) and xilazine (10mg/kg) anesthesia. After ventricular catheterization, analysis of left ventricular stiffness was made by pressure-volume curve (P-V). Results. Myocardial infarction size measured 24 hours after coronary occlusion was decreased by G-CSF pretreatment (35.8±2.8 vs. 43.7±2.1 IM; p<0.05). Moreover, 15 days after coronary occlusion, the myocardial infarction was reduced in the IM-GCSF group as compare to IM group (27,2±2,2% vs. 35,9±1,4%, p<0,05). The treatment with G-CSF increase the protein expression of Bcl-2 (8.8±0.9 vs. 5.2±0.6 in IM group, p<0.05), Bcl-xL (5.6±0.8 vs. 3±0.2 in IM group, p<0.05), but doesn’t change Bax expression (5.9±1 vs. 5.5±1.2 in IM group, p>0.05). In the first 24 hours after infarction, mortality was significantly reduced by G-CSF pretreatment (26% vs. 47%, p<0.05), being the reduction more prominent at the first 30 minutes after occlusion (11% vs. 27.6%, p<0.05). The number of events (7±2 vs 29±6, p<0.05) and the duration (13±4 s vs. 43±9 s, p<0.05) of VT were reduced in the animals of IM-GCSF group, as well as the incidence of VF (10% vs 69%, p<0.05). IM group presents less ventricular stiffness as compared to other groups in a initial phase (k=19.9±2.5 vs. k=41±5 in IM-GCSF group and k=42.8±3.5 in Sham group, p<0.05), but at high pressure, the ventricular stiffness in IM only differs from IMGCSF group (k=2.52±0.2, IM; k=3.35±0.2, IM-GCSF; k=3.02±0.7, Sham; p<0.05). Conclusions. The pretreatment with G-CSF was effective in reducing myocardial infarction size evaluated soon after coronary occlusion and this difference was maintained throughout 15 days after occlusion. This result is due to an increase in expression of antiapoptotical factors, reducing the ischemic injury in the initial phase of myocardial infarction. Moreover, the increase in connexin43 expression in pretreated group seems to be responsible for the decrease in ventricular arrhythmias, leading to an important reduction in mortality rate soon after myocardial infarction. All of these results seem to contribute to hemodynamic preservation found 15 days after coronary occlusion in animals that received G-CSF.