MECHANISM OF THE CARDIOPROTECTIVE EFFECT OF TRANSFORMING GROWTH FACTOR-BETA-1 IN FELINE MYOCARDIAL-ISCHEMIA AND REPERFUSION

We studied the effects of transforming growth factor beta1 (TGF-beta1) in a feline model of myocardial ischemia (1.5 hr) and reperfusion (4.5 hr). Myocardial ischemia followed by reperfusion resulted in severe myocardial injury, endothelial dysfunction, high cardiac myeloperoxidase activity indicative of neutrophil accumulation in the ischemic myocardium, and significant neutrophil adherence to the ischemic coronary endothelium. In contrast, intravenous administration of TGF-beta1 (20 mug/kg) 30 min prior to reperfusion significantly attenuated myocardial necrosis (13.8% +/- 3.5% vs. 32.2% +/- 2.9% of area-at-risk, P < 0.01) and attenuated endothelial dysfunction (P < 0.01) associated with ischemia-reperfusion. Moreover, myeloperoxidase activity in the ischemic myocardium was significantly lower than vehicle controls (0.2 +/- 0.1 vs. 1.7 +/- 0.3 units/100 mg of tissue, P < 0.01) and neutrophil adherence to ischemic coronary endothelium was significantly (P < 0.01) attenuated in TGF-beta1-treated cats. These results demonstrate that TGF-beta1 exerts a significant cardioprotective effect in a feline model of myocardial ischemia and reperfusion. The mechanism of this protective effect appears to relate to endothelial preservation by TGF-beta1 inhibiting circulating neutrophils from adhering to the endothelium, a critical step in neutrophil-induced reperfusion injury.

我们在猫心肌缺血（1.5小时）和再灌注（4.5小时）模型中研究了转化生长因子β1（TGF -β1）的作用。心肌缺血后再灌注导致严重的心肌损伤、内皮功能障碍、提示中性粒细胞在缺血心肌中积聚的高心脏髓过氧化物酶活性，以及中性粒细胞对缺血冠状动脉内皮的显著黏附。相比之下，在再灌注前30分钟静脉注射TGF -β1（20μg/kg）显著减轻了心肌坏死（危险区域的13.8%±3.5%对比32.2%±2.9%，P < 0.01），并减轻了与缺血 - 再灌注相关的内皮功能障碍（P < 0.01）。此外，缺血心肌中的髓过氧化物酶活性显著低于溶媒对照组（0.2±0.1对比1.7±0.3单位/100mg组织，P < 0.01），并且在TGF -β1处理的猫中，中性粒细胞对缺血冠状动脉内皮的黏附显著（P < 0.01）减轻。这些结果表明，TGF -β1在猫心肌缺血和再灌注模型中具有显著的心脏保护作用。这种保护作用的机制似乎与TGF -β1通过抑制循环中性粒细胞黏附于内皮从而保护内皮有关，这是中性粒细胞诱导的再灌注损伤中的关键步骤。