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首页> 外文期刊>Journal of Cellular Physiology >Lipocalin-2 (NGAL) Attenuates Autophagy to Exacerbate Cardiac Apoptosis Induced by Myocardial Ischemia
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Lipocalin-2 (NGAL) Attenuates Autophagy to Exacerbate Cardiac Apoptosis Induced by Myocardial Ischemia

机译：Lipocalin-2 (NGAL)变弱自噬加重心脏引起的细胞凋亡心肌缺血

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Lipocalin-2 (Lcn2; also termed neutrophil gelatinase-associated lipocalin (NGAL)) levels correlate positively with heart failure (HF) yet mechanisms via which Lcn2 contributes to the pathogenesis of HF remain unclear. In this study, we used coronary artery ligation surgery to induce ischemia in wild-type (wt) mice and this induced a significant increase in myocardial Lcn2. We then compared wt and Lcn2 knockout (KO) mice and observed that wt mice showed greater ischemia-induced caspase-3 activation and DNA damage measured by TUNEL than Lcn2KO mice. Analysis of autophagy by LC3 and p62 Western blotting, LC3 immunohistochemistry and transmission electron microscopy (TEM) indicated that Lcn2 KO mice had a greater ischemia-induced increase in autophagy. Lcn2KO were protected against ischemia-induced cardiac functional abnormalities measured by echocardiography. Upon treating a cardiomyocyte cell line (h9c2) with Lcn2 and examining AMPK and ULK1 phosphorylation, LC3 and p62 by Western blot as well as tandem fluorescent RFP/GFP-LC3 puncta by immunofluorescence, MagicRed assay for lysosomal cathepsin activity and TEM we demonstrated that Lcn2 suppressed autophagic flux. Lcn2 also exacerbated hypoxia-induced cytochromc c release from mitochondria and caspase-3 activation. We generated an autophagy-deficient H9c2 cell model by overexpressing dominant-negative Atg5 and found significantly increased apoptosis after Lcn2 treatment. In summary, our data indicate that Lcn2 can suppress the beneficial cardiac autophagic response to ischemia and that this contributes to enhanced ischemia-induced cell death and cardiac dysfunction. J. Cell. Physiol. 232: 2125-2134, 2017. (c) 2016 Wiley Periodicals, Inc.
机译：Lipocalin-2 (Lcn2;gelatinase-associated lipocalin (NGAL))的水平正相关与心力衰竭(HF)通过这Lcn2有利于机制心力衰竭的发病机制尚不清楚。我们使用冠状动脉结扎手术诱导缺血在野生型小鼠(wt)诱导心肌的显著增加Lcn2。老鼠和观察到wt老鼠大ischemia-induced caspase-3激活和DNATUNEL测量的损害比Lcn2KO老鼠。分析LC3的自噬和p62西方印迹,LC3免疫组织化学透射电子显微镜(TEM)表示, Lcn2 KO小鼠ischemia-induced更大自噬的增加。针对ischemia-induced心脏功能通过超声心动图异常测量。治疗心肌细胞细胞系(h9c2)Lcn2检查AMPK和ULK1磷酸化,LC3和p62免疫印迹以及串联荧光RFP / GFP-LC3 puncta免疫荧光,MagicRed测定溶酶体组织蛋白酶活性和TEM我们证明Lcn2抑制自噬流量。加剧了低氧诱导cytochromc c版本从线粒体和caspase-3激活。生成一个autophagy-deficient H9c2细胞模型由overexpressing显性负Atg5和发现后显著增加细胞凋亡Lcn2治疗。Lcn2可以抑制有益心脏自噬对缺血,这回应有助于增强ischemia-induced细胞死亡和心脏功能障碍。232: 2125 - 2134, 2017。公司。

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