Role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in oxygen sensing and constriction of the ductus arteriosus.
Role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in oxygen sensing and constriction of the ductus arteriosus.
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DOI：
10.1161/circresaha.111.300285
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发表时间：
2013-03-01
影响因子：
20.1
通讯作者：
Archer SL
中科院分区：
文献类型：
--
作者：
Hong Z;Kutty S;Toth PT;Marsboom G;Hammel JM;Chamberlain C;Ryan JJ;Zhang HJ;Sharp WW;Morrow E;Trivedi K;Weir EK;Archer SL
动脉导管(DA)的关闭对于从胎儿循环模式向新生儿循环模式的转变至关重要。最初的PO2依赖的血管收缩会在几分钟内导致功能性DA关闭。几天内，一种纤维化、增生性机制会导致解剖闭合。尽管受到内皮衍生的血管扩张剂和收缩药的调节，但氧感觉是导管平滑肌细胞(DASMC)固有的，氧诱导的DA收缩在缺乏内皮、内皮素和环氧合酶介质的情况下持续存在。O2增加线粒体衍生的过氧化氢(MitoROS)，而线粒体衍生的过氧化氢通过升高细胞内钙和激活Rho激酶而收缩DASMC。然而，氧改变线粒体功能的机制尚不清楚。确定线粒体分裂是否是O2诱导的DA收缩和闭合的关键。利用在先天性心脏病矫正期间从30名足月婴儿身上获取的DA，以及从足月兔身上获取的DA，我们证明了线粒体分裂在O2诱导的收缩和闭合中起着关键作用。氧气迅速(5分钟)通过细胞周期蛋白依赖的激酶介导的丝氨酸616处的动力蛋白相关蛋白1(Drp1)的磷酸化导致线粒体分裂。分裂触发DASMC的代谢转变，激活丙酮酸脱氢酶并增加线粒体过氧化氢的产生。随后，裂变增加了复杂的I活性。线粒体靶向过氧化氢酶的过度表达消除了PO2诱导的线粒体ROS和细胞内钙的增加。小分子DRp1抑制剂Mdivi-1和siDRP1产生一致的结果，抑制O2诱导的收缩(不改变对苯肾上腺素或KCl的反应)，并防止O2诱导的氧化代谢、细胞内钙和DASMC增殖增加。在组织培养模型中，长期抑制Drp1可减少DA的闭合。线粒体分裂是哺乳动物氧气感应的一个必需的早期步骤，为调节DA开放提供了一个很有前途的靶点。
Closure of the ductus arteriosus (DA) is essential for the transition from fetal to neonatal patterns of circulation. Initial PO2-dependent vasoconstriction causes functional DA closure within minutes. Within days a fibrogenic, proliferative mechanism causes anatomical closure. Though modulated by endothelial-derived vasodilators and constrictors, O2-sensing is intrinsic to ductal smooth muscle cells (DASMC) and oxygen-induced DA constriction persists in the absence of endothelium, endothelin and cyclooxygenase mediators. O2 increases mitochondrial-derived H2O2 (mitoROS), which constricts DASMC by raising intracellular calcium and activating rho kinase. However, the mechanism by which oxygen changes mitochondrial function is unknown. Determine whether mitochondrial fission is crucial for O2-induced DA constriction and closure. Using DA harvested from 30 term infants during correction of congenital heart disease, as well as DA from term rabbits, we demonstrate that mitochondrial fission is crucial for O2-induced constriction and closure. O2 rapidly (<5 minutes) causes mitochondrial fission by a cyclin-dependent kinase-mediated phosphorylation of dynamin-related protein 1 (Drp1) at serine 616. Fission triggers a metabolic shift in the DASMC that activates pyruvate dehydrogenase and increases mitochondrial H2O2 production. Subsequently fission increases complex I activity. Mitochondrial-targeted catalase overexpression eliminates PO2-induced increases in mitoROS and cytosolic calcium. The small-molecule Drp1 inhibitor, Mdivi-1, and siDRP1 yield concordant results, inhibiting O2-induced constriction (without altering the response to phenylephrine or KCl) and preventing O2-induced increases in oxidative metabolism, cytosolic calcium and DASMC proliferation. Prolonged Drp1 inhibition reduces DA closure in a tissue culture model. Mitochondrial fission is an obligatory, early step in mammalian O2-sensing and offers a promising target for modulating DA patency.