Murray Andrew J, Lygate Craig A, Cole Mark A, Carr Carolyn A, Radda George K, Neubauer Stefan, Clarke Kieran
University Laboratory of Physiology, University of Oxford, Parks Rd., Oxford, OX1 3PT, England, UK.
Cardiovasc Res. 2006 Jul 1;71(1):149-57. doi: 10.1016/j.cardiores.2006.02.031. Epub 2006 Mar 10.
Many patients with heart failure have whole-body insulin resistance and reduced cardiac fluorodeoxyglucose uptake, but whether these metabolic changes have detrimental effects on the heart is unknown. Here, we tested whether there is a link between insulin resistance and ischemic damage in the chronically infarcted Wistar rat heart, postulating that the heart would have decreased insulin sensitivity, with lower GLUT4 glucose transporter protein levels due to high circulating free fatty acid (FFA) concentrations. A decreased capacity for glucose uptake would lower glycolytic adenosine triphosphate (ATP) production and thereby increase ischemic injury in the infarcted heart.
In vivo left ventricular ejection fractions, measured using echocardiography, were 40% lower in rats 10 weeks after coronary artery ligation than in sham-operated control rats. Insulin-stimulated D[2-3H]glucose uptake was 42% lower in isolated, perfused, infarcted hearts. Myocardial GLUT4 glucose transporter protein levels were 28% lower in the infarcted hearts and correlated negatively with ejection fractions and with fasting plasma FFA concentrations. Compared with controls, chronically infarcted hearts had 46% lower total glucose uptake and three-fold faster ATP hydrolysis rates, measured using phosphorus-31 nuclear magnetic resonance spectroscopy, during 32-min ischemia at 0.4 ml/min/gww. During reperfusion, recovery of left ventricular developed pressure in infarcted hearts was 42% lower than in control hearts.
Glucose uptake, in response to insulin or ischemia, was lower in the chronically infarcted rat heart and associated with increased circulating FFA concentrations and decreased GLUT4 levels. Thus, infarcted hearts had greater ATP depletion, and consequently incurred greater damage, during ischemia.
许多心力衰竭患者存在全身胰岛素抵抗且心肌氟脱氧葡萄糖摄取减少，但这些代谢变化是否对心脏产生有害影响尚不清楚。在此，我们测试了慢性梗死的Wistar大鼠心脏中胰岛素抵抗与缺血损伤之间是否存在联系，推测由于循环中游离脂肪酸（FFA）浓度较高，心脏的胰岛素敏感性会降低，葡萄糖转运蛋白4（GLUT4）水平也会降低。葡萄糖摄取能力下降会降低糖酵解三磷酸腺苷（ATP）的产生，从而增加梗死心脏的缺血损伤。
使用超声心动图测量，冠状动脉结扎10周后的大鼠左心室射血分数比假手术对照组大鼠低40%。在离体灌注的梗死心脏中，胰岛素刺激的D-[2-3H]葡萄糖摄取降低了42%。梗死心脏中GLUT4葡萄糖转运蛋白水平降低了28%，且与射血分数和空腹血浆FFA浓度呈负相关。与对照组相比，在0.4 ml/min/gww的条件下进行32分钟缺血期间，使用磷-31核磁共振波谱测量，慢性梗死心脏的总葡萄糖摄取降低了46%，ATP水解速率快了三倍。在再灌注期间，梗死心脏左心室舒张末压的恢复比对照心脏低42%。
在慢性梗死的大鼠心脏中，胰岛素或缺血刺激后的葡萄糖摄取较低，且与循环FFA浓度升高和GLUT4水平降低有关。因此，梗死心脏在缺血期间ATP消耗更大，从而遭受更大的损伤。
