Apolipoprotein A-1 mimetic D-4F enhances isoflurane-induced eNOS signaling and cardioprotection during acute hyperglycemia
Apolipoprotein A-1 mimetic D-4F enhances isoflurane-induced eNOS signaling and cardioprotection during acute hyperglycemia
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DOI：
10.1152/ajpheart.00850.2012
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发表时间：
2013-07-01
影响因子：
4.8
通讯作者：
Kersten, Judy R.
中科院分区：
文献类型：
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作者：
Baotic, Ines;Ge, Zhi-Dong;Kersten, Judy R.
急性高血糖 (AHG) 会降低一氧化氮 (NO) 的利用率，并损害麻醉预处理 (APC) 引起的心肌梗死保护作用。我们研究了 D-4F（一种载脂蛋白 A-1 模拟物）是否通过在 AHG 期间促进 APC 诱导的内皮 NO 信号传导来拯救心肌。在存在或不存在 APC [异氟烷 (1.4%)] 的情况下，在有或没有 AHG [葡萄糖 (2 g/kg ip)] 和 D-4F（0.12 或 0.6 mg/kg ip）的情况下测量小鼠的心肌梗塞大小。在存在或不存在 D-4F (0.5 μg/ml) 的情况下，在含有或不含有异氟烷 (0.5 mM) 的 5.5 或 20 mM 葡萄糖中培养的人冠状动脉内皮细胞中，评估 NO 产生、超氧化物生成、蛋白质区室化和翻译后内皮 NO 合酶 (eNOS) 修饰。与对照组（54 +/- 3%）相比，在不存在但不存在 AHG（49 +/- 4%）的情况下，APC 显着减少了心肌梗塞面积（风险区域的 36 +/- 3%）。 D-4F 在 AHG 期间恢复了 APC 的心脏保护作用（分别为 36 +/- 3% 和 30 +/- 3%、0.12 和 0.6 mg/kg），尽管单独使用 D-4F 对梗塞面积没有影响（53 +/- 3%）。异氟醚促进内皮细胞小凹内的caveolin-1和eNOS区室化以及eNOS二聚化，同时NO产生增加（对照中为411+/-28 vs. 68+/-10pmol/mg蛋白质）。这些作用被 AHG 减弱（NO 产生：264 +/- 18 pmol/mg 蛋白质）。 D-4F 减少超氧化物的产生，增强 Caveolin-1 和 eNOS 小穴区室化和翻译后 eNOS 修饰，从而恢复异氟烷和 AHG 过程中 NO 的产生（418 +/- 36 pmol/mg 蛋白质）。总之，D-4F 在 AHG 期间恢复了 APC 的心脏保护作用，可能是通过减少超氧化物的产生来促进异氟烷诱导的 eNOS 信号传导和 NO 生物合成。
Acute hyperglycemia (AHG) decreases the availability of nitric oxide (NO) and impairs anesthetic preconditioning (APC)-elicited protection against myocardial infarction. We investigated whether D-4F, an apolipoprotein A-1 mimetic, rescues the myocardium by promoting APC-induced endothelial NO signaling during AHG. Myocardial infarct size was measured in mice in the absence or presence of APC [isoflurane (1.4%)] with or without AHG [dextrose (2 g/kg ip)] and D-4F (0.12 or 0.6 mg/kg ip). NO production, superoxide generation, protein compartmentalization, and posttranslational endothelial NO synthase (eNOS) modifications were assessed in human coronary artery endothelial cells cultured in 5.5 or 20 mM glucose with or without isoflurane (0.5 mM) in the presence or absence of D-4F (0.5 mu g/ml). Myocardial infarct size was significantly decreased by APC (36 +/- 3% of risk area) compared with control (54 +/- 3%) in the absence, but not presence, of AHG (49 +/- 4%). D-4F restored the cardioprotective effect of APC during AHG (36 +/- 3% and 30 +/- 3%, 0.12 and 0.6 mg/kg, respectively), although D-4F alone had no effect on infarct size (53 +/- 3%). Isoflurane promoted caveolin-1 and eNOS compartmentalization within endothelial cell caveolae and eNOS dimerization, concomitant with increased NO production (411 +/- 28 vs. 68 +/- 10 pmol/mg protein in control). These actions were attenuated by AHG (NO production: 264 +/- 18 pmol/mg protein). D-4F reduced superoxide generation and enhanced caveolin-1 and eNOS caveolar compartmentalization and posttranslational eNOS modifications, thus restoring NO production during isoflurane and AHG (418 +/- 36 pmol/mg protein). In conclusion, D-4F restored the cardioprotective effect of APC during AHG, possibly by decreasing superoxide generation, which promoted isoflurane-induced eNOS signaling and NO biosynthesis.