Improved myocardial perfusion in chronic diabetic mice by the up-regulation of pLKB1 and AMPK signaling.
Improved myocardial perfusion in chronic diabetic mice by the up-regulation of pLKB1 and AMPK signaling.
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DOI：
10.1002/jcb.22486
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发表时间：
2010-04-01
影响因子：
4
通讯作者：
Abraham, Nader G.
中科院分区：
文献类型：
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作者：
Kusmic, Claudia;L'Abbate, Antonio;Sambuceti, Gianmario;Drummond, George;Barsanti, Cristina;Matteucci, Marco;Cao, Jian;Piccolomini, Francesco;Cheng, Jennifer;Abraham, Nader G.
关键词：
先前的研究将糖尿病心肌微循环受损与氧化应激和内皮功能障碍联系起来。因此，本研究旨在确定上调pAMPK-pAKT信号传导对糖尿病小鼠离体心脏中冠状动脉微血管反应性的影响。我们测量了灌注压变化期间野生型和链脲佐菌素（STZ）治疗小鼠的冠状动脉阻力。测定血浆中葡萄糖、胰岛素和脂联素水平以及心肌组织中超氧化物生成、NOx水平和血红素氧合酶（HO）活性。此外，HO-1，3-硝基酪氨酸，pLKB 1，pAMPK，pAKT，和peNOS蛋白的表达在控制和糖尿病心脏进行了测量。冠状动脉对灌注压变化的反应在STZ给药后以时间依赖性方式偏离对照。在糖尿病28周（检查的最长时间）观察到的反应通过L-NAME给药模拟对照动物，并与血清脂联素和心肌pLKB 1，pAMPK，pAKT和pGSK-3表达的降低相关。钴原卟啉治疗诱导HO-1表达逆转了糖尿病患者的微血管反应性。HO-1的上调与脂联素、pLKB 1、pAKT、pAMPK、pGSK-3和peNOS水平的增加以及心肌超氧化物和3-硝基酪氨酸水平的降低相关。在本研究中，我们描述了糖尿病发展过程中微血管功能变化的时间过程，以及糖尿病心脏中血清脂联素、pLKB 1、pAKT和pAMPK激活水平之间存在的独特关系。微血管功能的恢复为糖尿病晚期心脏微血管紊乱提供了一种新的治疗方法。
Previous studies related impaired myocardial microcirculation in diabetes to oxidative stress and endothelial dysfunction. Thus, this study was aimed to determine the effect of up-regulating pAMPK-pAKT signaling on coronary microvascular reactivity in the isolated heart of diabetic mice. We measured coronary resistance in wild-type and streptozotocin (STZ)-treated mice, during perfusion pressure changes. Glucose, insulin, and adiponectin levels in plasma and superoxide formation, NOx levels and heme oxygenase (HO) activity in myocardial tissue were determined. In addition, the expression of HO-1, 3-nitrotyrosine, pLKB1, pAMPK, pAKT, and peNOS proteins in control and diabetic hearts were measured. Coronary response to changes in perfusion pressure diverged from control in a time-dependent manner following STZ administration. The responses observed at 28 weeks of diabetes (the maximum time examined) were mimicked by L-NAME administration to control animals and were associated with a decrease in serum adiponectin and myocardial pLKB1, pAMPK, pAKT, and pGSK-3 expression. Cobalt protoporphyrin treatment to induce HO-1 expression reversed the microvascular reactivity seen in diabetes towards that of controls. Up-regulation of HO-1 was associated with an increase in adiponectin, pLKB1, pAKT, pAMPK, pGSK-3, and peNOS levels and a decrease in myocardial superoxide and 3-nitrotyrosine levels. In the present study we describe the time course of microvascular functional changes during the development of diabetes and the existence of a unique relationship between the levels of serum adiponectin, pLKB1, pAKT, and pAMPK activation in diabetic hearts. The restoration of microvascular function suggests a new therapeutic approach to even advanced cardiac microvascular derangement in diabetes.
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影响因子：
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作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
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