Jones Steven P, Greer James J M, Kakkar Aman K, Ware P Derek, Turnage Richard H, Hicks Michael, van Haperen Rien, de Crom Rini, Kawashima Seinosuke, Yokoyama Mitsuhiro, Lefer David J
Department of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
Am J Physiol Heart Circ Physiol. 2004 Jan;286(1):H276-82. doi: 10.1152/ajpheart.00129.2003. Epub 2003 Sep 11.
Previous studies indicate that deficiency of endothelial nitric oxide (NO) synthase (eNOS)-derived NO exacerbates myocardial reperfusion injury. We hypothesized that overexpression of eNOS would reduce the extent of myocardial ischemia-reperfusion (MI/R) injury. We investigated two distinct strains of transgenic (TG) mice overexpressing the eNOS gene (eNOS TG). Bovine eNOS was overexpressed in one strain (eNOS TG-Kobe), whereas the human eNOS gene was overexpressed in the other strain (eNOS TG-RT). Non-TG (NTG) and eNOS TG mice were subjected to 30 min of coronary artery occlusion followed by 24 h of reperfusion, and the extent of myocardial infarction was determined. Myocardial infarct size was reduced by 33% in the eNOS TG-Kobe strain (P < 0.05 vs. NTG) and by 32% in the eNOS TG-RT strain (P < 0.05 vs. NTG). However, postischemic cardiac function (cardiac output, fractional shortening) was not improved in the eNOS TG-Kobe mouse at 24 h of reperfusion [P = not significant (NS) vs. NTG]. In additional studies, eNOS TG-Kobe mice were subjected to 30 min of myocardial infarction and 7 days of reperfusion. Fractional shortening and the first derivative of left ventricular pressure were measured in eNOS TG-Kobe and NTG mice, and no significant differences in contractility were observed (P = NS) between the eNOS TG mice and NTG controls. Left ventricular end-diastolic pressure was significantly (P < 0.05 vs. NTG) reduced in the eNOS TG-Kobe strain at 7 days of reperfusion. The cardioprotective effects of eNOS overexpression on myocardial infarct size were ablated by Nomega-nitro-l-arginine methyl ester (300 mg/kg) pretreatment. Thus genetic overexpression of eNOS in mice attenuates myocardial infarction after MI/R but fails to significantly protect against postischemic myocardial contractile dysfunction in mice.
先前的研究表明，内皮型一氧化氮（NO）合酶（eNOS）衍生的NO缺乏会加剧心肌再灌注损伤。我们假设eNOS的过表达会减轻心肌缺血-再灌注（MI/R）损伤的程度。我们研究了两种不同品系的过表达eNOS基因的转基因（TG）小鼠（eNOS TG）。牛eNOS在一个品系（eNOS TG-神户）中过表达，而人eNOS基因在另一个品系（eNOS TG-RT）中过表达。非TG（NTG）和eNOS TG小鼠经历30分钟冠状动脉闭塞，随后再灌注24小时，并测定心肌梗死范围。eNOS TG-神户品系的心肌梗死面积减少了33%（与NTG相比，P<0.05），eNOS TG-RT品系减少了32%（与NTG相比，P<0.05）。然而，在再灌注24小时时，eNOS TG-神户小鼠的缺血后心功能（心输出量、缩短分数）并未改善[与NTG相比，P=无显著性差异（NS）]。在额外的研究中，eNOS TG-神户小鼠经历30分钟心肌梗死和7天再灌注。在eNOS TG-神户和NTG小鼠中测量缩短分数和左心室压力的一阶导数，在eNOS TG小鼠和NTG对照之间未观察到收缩性的显著差异（P=NS）。在再灌注7天时，eNOS TG-神户品系的左心室舒张末期压力显著降低（与NTG相比，P<0.05）。用Nω-硝基-L-精氨酸甲酯（300mg/kg）预处理可消除eNOS过表达对心肌梗死面积的心脏保护作用。因此，小鼠中eNOS的基因过表达可减轻MI/R后的心肌梗死，但未能显著预防小鼠缺血后心肌收缩功能障碍。
