Netrin-1 improves post-injury cardiac function in vivo via DCC/NO-dependent preservation of mitochondrial integrity, while attenuating autophagy.
Netrin-1 improves post-injury cardiac function in vivo via DCC/NO-dependent preservation of mitochondrial integrity, while attenuating autophagy.
复制标题
Netrin-1通过DCC/无依赖性线粒体完整性的保存在体内改善后心脏功能，同时减弱自噬。
DOI：
10.1016/j.bbadis.2014.06.005
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发表时间：
2015-02
影响因子：
6.2
通讯作者：
Cai, Hua
中科院分区：
文献类型：
--
作者：
Bouhidel, Jalaleddinne Omar;Wang, Ping;Siu, Kin Lung;Li, Hong;Youn, Ji Youn;Cai, Hua
关键词：
心脏再灌注损伤是急性心肌缺血血管成形术治疗的严重并发症，目前尚无治疗方法。本研究旨在确定一种新的蛋白netrin-1是否以及如何在体内诱导缺血/再灌注（I/R）损伤的心脏保护作用。使野生型（WT）C57 BL 6/J小鼠经受30分钟冠状动脉闭塞，随后用载体（生理盐水）、netrin-1、UO 126（MEK 1/2抑制剂）、PTIO（一氧化氮/NO清除剂）、netrin-1/UO 126或netrin-1/PTIO心室内再灌注24小时。尾静脉注射netrin-1。5 μg/kg的Netrin-1诱导了梗死面积的显著减小（从对照组的41.3±1.8%减少19.7±5.0%），并且通过超声心动图测量的射血分数和缩短分数显著改善了心脏功能。netrin-1受体DCC缺陷小鼠（在结直肠癌中缺失，DCC+/−）或netrin-1/UO 126或netrin-1/PTIO再灌注小鼠的实验减弱了netrin-1的保护作用，暗示DCC，ERK 1/2和NO的中间作用。Netrin-1诱导的ERK 1/2和eNOS磷酸化在DCC+/−小鼠中被消除。电子自旋共振（ESR）测定离体左心室的NO产生表明，netrin-1提高NO的生物利用度，这是由UO 126或DCC+/−小鼠减弱，这表明DCC和ERK 1/2在NO产生的上游作用。Netrin-1进一步降低了线粒体肿胀和线粒体超氧化物的产生，当与PTIO或UO 126共处理时，或在DCC+/−小鼠中，这是不存在的，表明DCC，ERK 1/2和NO在保持线粒体完整性方面的关键作用。在心肌梗死（MI）的永久性冠状动脉结扎模型中评估MI后重塑，netrin-1消除了自噬的显着增加。总之，我们的数据表明netrin-1在体内具有强大的心脏保护作用，如梗死面积减少和心脏功能改善所示。从机制上讲，这种保护是由netrin-1受体DCC介导的，并且线粒体的NO依赖性保存。这项工作清楚地确立了netrin-1用于急性治疗MI的治疗潜力，也许还用于慢性MI后重塑。
Reperfusion injury of the heart is a severe complication of angioplasty treatment of acute myocardial ischemia, for which no therapeutics are currently available. The present study aimed to identify whether and how a novel protein netrin-1 induces cardioprotection in vivo during ischemia/reperfusion (I/R) injury. Wild type (WT) C57BL6/J mice were subjected to a 30 min coronary occlusion followed by a 24 hr reperfusion with vehicle (normal saline), netrin-1, UO126 (MEK1/2 inhibitor), PTIO (nitric oxide/NO scavenger), netrin-1/UO126 or netrin-1/PTIO intraventricularly. Some were injected of netrin-1 via tail vein. Netrin-1 at 5 μg/kg induced a substantial reduction in infarct size (19.7±5.0% from 41.3±1.8% in the controls), and markedly improved cardiac function as measured by ejection fraction and fractional shortening from echocardiography. Experiments with mice deficient in netrin-1 receptor DCC (deleted in colorectal cancer, DCC+/−), or reperfusion with netrin-1/UO126 or netrin-1/PTIO, attenuated the protective effects of netrin-1, implicating intermediate roles of DCC, ERK1/2 and NO. Netrin-1 induced phosphorylation of ERK1/2 and eNOS was abolished in DCC+/− mice. Electron spin resonance (ESR) determination of NO production from isolated left ventricles demonstrated that netrin-1 improves NO bioavailbility, which was attenuated by UO126 or in DCC+/− mice, suggesting upstream roles of DCC and ERK1/2 in NO production. Netrin-1 further reduced mitochondrial swelling and mitochondrial superoxide production, which was absent when co-treated with PTIO or UO126, or in DCC+/− mice, indicating critical roles of DCC, ERK1/2 and NO in preserving mitochondrial integrity. In a permanent coronary ligation model of myocardial infarction (MI) to assess post-MI remodeling, netrin-1 abolished the marked increase in autophagy. In summary, our data demonstrate robust cardioprotective effect of netrin-1 in vivo, as shown by reduced infarct size and improved cardiac function. Mechanistically, this protection is mediated by netrin-1 receptor DCC, and NO dependent preservation of mitochondria. This work clearly establishes a therapeutic potential of netrin-1 for acute treatment of MI, perhaps also for chronic post-MI remodeling.
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影响因子：
37.8
作者：
Go AS;Mozaffarian D;Roger VL;Benjamin EJ;Berry JD;Blaha MJ;Dai S;Ford ES;Fox CS;Franco S;Fullerton HJ;Gillespie C;Hailpern SM;Heit JA;Howard VJ;Huffman MD;Judd SE;Kissela BM;Kittner SJ;Lackland DT;Lichtman JH;Lisabeth LD;Mackey RH;Magid DJ;Marcus GM;Marelli A;Matchar DB;McGuire DK;Mohler ER 3rd;Moy CS;Mussolino ME;Neumar RW;Nichol G;Pandey DK;Paynter NP;Reeves MJ;Sorlie PD;Stein J;Towfighi A;Turan TN;Virani SS;Wong ND;Woo D;Turner MB;American Heart Association Statistics Committee and Stroke Statistics Subcommittee
通讯作者：
American Heart Association Statistics Committee and Stroke Statistics Subcommittee
影响因子：
20.1
作者：
Gustafsson AB;Gottlieb RA
通讯作者：
Gottlieb RA
DOI：
10.1152/ajpheart.1999.276.5.h1567
发表时间：
1999-05-01
影响因子：
4.8
作者：
Jones, SP;Girod, WG;Lefer, DJ
通讯作者：
Lefer, DJ
影响因子：
15.9
作者：
Mungrue, IN;Gros, R;Husain, M
通讯作者：
Husain, M
影响因子：
64.8
作者：
Baines, CP;Kaiser, RA;Molkentin, JD
通讯作者：
Molkentin, JD