Mitochondrial transporter ATP binding cassette mitochondrial erythroid is a novel gene required for cardiac recovery after ischemia/reperfusion.
Mitochondrial transporter ATP binding cassette mitochondrial erythroid is a novel gene required for cardiac recovery after ischemia/reperfusion.
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DOI：
10.1161/circulationaha.110.003418
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发表时间：
2011-08-16
期刊：
影响因子：
37.8
通讯作者：
Shirihai OS
中科院分区：
文献类型：
--
作者：
Liesa M;Luptak I;Qin F;Hyde BB;Sahin E;Siwik DA;Zhu Z;Pimentel DR;Xu XJ;Ruderman NB;Huffman KD;Doctrow SR;Richey L;Colucci WS;Shirihai OS
氧化应激和线粒体功能障碍是缺血再灌注后心脏功能障碍的主要介质。 ABC-me (ABCB10/mABC2) 是一种在红系分化过程中高度诱导的线粒体转运蛋白，主要在骨髓、肝脏和心脏中表达。然而，ABC-me 在心脏中的功能尚不清楚。多项证据表明 ABC-me 的酵母直系同源物可防止氧化应激增加。因此，ABC-me 是心脏缺血再灌注结果的潜在调节剂。通过用新霉素抗性盒替换 ABC-me 外显子 2 和 3，产生了携带 ABC-me 一种功能性等位基因 (ABC-me +/-) 的小鼠。使用 Langendorff 灌注和超声心动图评估心脏功能。在基础条件下，ABC-me+/-小鼠具有正常的心脏结构、血流动力学功能、线粒体呼吸和氧化状态。然而，缺血再灌注后，由于收缩和舒张功能受损，ABC-me +/- 心脏的血流动力学功能恢复降低了 50%。这种减少与线粒体生物能功能受损以及再灌注后线粒体脂质和肌浆网钙 ATP 酶 (SERCA) 的氧化损伤有关。用超氧化物歧化酶/过氧化氢酶模拟物 EUK-207 治疗 ABC-me +/- 心脏可防止线粒体和 SERCA 的氧化损伤，并在再灌注后将线粒体和心脏功能恢复至野生型水平。 ABC-me 的一个等位基因失活会增加对缺血再灌注引起的氧化应激的敏感性，导致线粒体和 SERCA 的氧化损伤增加，并导致功能恢复受损。因此，ABC-me是一种决定心脏缺血再灌注耐受能力的新基因。
Oxidative stress and mitochondrial dysfunction are central mediators of cardiac dysfunction following ischemia-reperfusion. ABC-me (ABCB10/mABC2) is a mitochondrial transporter highly induced during erythroid differentiation and predominantly expressed in bone marrow, liver and heart. However, ABC-me function in heart is unknown. Several lines of evidence demonstrate that the yeast orthologue of ABC-me protects from increased oxidative stress. Therefore, ABC-me is a potential modulator of the outcome of ischemia-reperfusion in the heart. Mice harboring one functional allele of ABC-me (ABC-me +/-) were generated by replacing ABC-me exons 2 and 3 by a neomycin resistance cassette. Cardiac function was assessed using Langendorff perfusion and echocardiography. Under basal conditions, ABC-me +/- mice had normal heart structure, hemodynamic function, mitochondrial respiration and oxidative status. However, following ischemia-reperfusion, the recovery of hemodynamic function was reduced by 50% in ABC-me +/- hearts due to impairments in both systolic and diastolic function. This reduction was associated with impaired mitochondrial bioenergetic function and with oxidative damage to both mitochondrial lipids and the sarcoplasmic reticulum calcium ATPase (SERCA) after reperfusion. Treatment of ABC-me +/- hearts with the superoxide dismutase/catalase mimetic EUK-207 prevented oxidative damage to mitochondria and SERCA, and restored mitochondrial and cardiac function to wild type levels after reperfusion. Inactivation of one allele of ABC-me increases the susceptibility to oxidative stress induced by ischemia-reperfusion, leading to increased oxidative damage to mitochondria and SERCA, and to impaired functional recovery. Thus, ABC-me is a novel gene that determines the ability to tolerate cardiac ischemia-reperfusion.