HDL protects against ischemia reperfusion injury by preserving mitochondrial integrity
HDL protects against ischemia reperfusion injury by preserving mitochondrial integrity
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DOI：
10.1016/j.atherosclerosis.2013.02.003
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发表时间：
2013-05-01
期刊：
影响因子：
5.3
通讯作者：
Lecour, Sandrine
中科院分区：
文献类型：
--
作者：
Frias, Miguel A.;Pedretti, Sarah;Lecour, Sandrine
目的：探讨高密度脂蛋白对缺血再灌注损伤（IRI）的保护作用。然而，确切的机制尚不清楚。新的内在促生存信号通路被称为幸存者激活因子增强（SAFE）通路，涉及肿瘤坏死因子(TNF) α和转录信号换能器和激活因子3 （STAT3）的激活。SAFE在抗IRI的心脏保护中起着至关重要的作用。我们提出HDL通过激活SAFE通路和调节线粒体通透性过渡孔（mPTP）开放来预防IRI。方法和结果：小鼠离体心脏局部缺血（35 min），再灌注（45 min）。在再灌注前7分钟给予HDL。在对照心脏中，再灌注后梗死面积为41.3±2.3%。再灌注期间添加HDL以剂量依赖的方式减少梗死面积（HDL 200 μ g蛋白/ml: 25.5 +/- 1.6%, p < 0.001）。这种保护作用在TNF缺陷小鼠（TNF- ko）或心肌细胞stat3缺陷小鼠（STAT3-KO）中不存在。同样，在模拟缺血的分离心肌细胞中，HDL作为预处理刺激可改善细胞存活并抑制mPTP开放。这些保护反应在TNF-KO和STAT3-KO小鼠心肌细胞中被抑制。结论：我们的数据表明HDL通过抑制mPTP开放来预防IRI，这种作用是通过激活SAFE途径介导的。2013爱思唯尔爱尔兰有限公司版权所有。
Objective: High density lipoproteins (HDL) protect against ischemia reperfusion injury (IRI). However the precise mechanisms are not clearly understood. The novel intrinsic prosurvival signaling pathway named survivor activating factor enhancement (SAFE) path involves the activation of tumor necrosis factor (TNF) alpha and signal transducer and activator of transcription 3 (STAT3). SAFE plays a crucial role in cardioprotection against IRI. We propose that HDL protect against IRI via activation of the SAFE pathway and modulation of the mitochondrial permeability transition pore (mPTP) opening.Methods and results: Isolated mouse hearts were subjected to global ischemia (35 min) followed by reperfusion (45 min). HDL were given during the first 7 min of reperfusion. In control hearts, the post-reperfusion infarct size was 41.3 +/- 2.3%. Addition of HDL during reperfusion reduced the infarct size in a dose-dependent manner (HDL 200 mu g protein/ml: 25.5 +/- 1.6%, p < 0.001 vs. control). This protective effect was absent in TNF deficient mice (TNF-KO) or cardiomyocyte-STAT3 deficient mice (STAT3-KO). Similarly, HDL, given as a preconditioning stimulus, improved cell survival and inhibited mPTP opening in isolated cardiomyocytes subjected to simulated ischemia. These protective responses were inhibited in cardiomyocytes from TNF-KO and STAT3-KO mice.Conclusion: Our data demonstrate that HDL protect against IRI by inhibition of mPTP opening, an effect mediated via activation of the SAFE pathway. (C) 2013 Elsevier Ireland Ltd. All rights reserved.