Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension.
Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension.
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DOI：
10.15252/emmm.201404511
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发表时间：
2015-06
影响因子：
11.1
通讯作者：
Chan SY
中科院分区：
文献类型：
--
作者：
White K;Lu Y;Annis S;Hale AE;Chau BN;Dahlman JE;Hemann C;Opotowsky AR;Vargas SO;Rosas I;Perrella MA;Osorio JC;Haley KJ;Graham BB;Kumar R;Saggar R;Saggar R;Wallace WD;Ross DJ;Khan OF;Bader A;Gochuico BR;Matar M;Polach K;Johannessen NM;Prosser HM;Anderson DG;Langer R;Zweier JL;Bindoff LA;Systrom D;Waxman AB;Jin RC;Chan SY
铁-硫(Fe-S)簇是线粒体代谢所必需的，但其在肺动脉高压(PH)中的调控仍是个谜。我们证明，miR210-ISCU1/2轴的改变在体内导致铁-S缺乏，并促进PH。在肺血管细胞，尤其是内皮细胞，低氧诱导miR-210和抑制miR-210靶向ISCU1/2下调Fe-S水平。在受PH影响的小鼠和人血管和内皮组织中，miR-210表达升高，并伴有ISCU1/2和Fe-S完整性降低。在小鼠中，miR-210抑制ISCU1/2，促进PH。MiR-210基因缺失的小鼠，通过遗传/药物手段或内皮特异性方式，表现出ISCU1/2增加，并对铁-S依赖的病理表型和PH耐药。与缺氧或miR-210过表达类似，ISCU1/2基因敲除也促进PH。最后，对一名ISCU纯合子突变女性进行的心肺运动测试显示，运动导致肺血管功能障碍。因此，在后天(缺氧)或遗传因素的驱动下，miR210-ISCU1/2调节轴是导致铁-S缺乏和PH的致病关键。这些发现对于定义PH的代谢起源和潜在的具有相似基础的其他代谢性疾病具有广泛的翻译意义。
Iron–sulfur (Fe-S) clusters are essential for mitochondrial metabolism, but their regulation in pulmonary hypertension (PH) remains enigmatic. We demonstrate that alterations of the miR-210-ISCU1/2 axis cause Fe-S deficiencies in vivo and promote PH. In pulmonary vascular cells and particularly endothelium, hypoxic induction of miR-210 and repression of the miR-210 targets ISCU1/2 down-regulated Fe-S levels. In mouse and human vascular and endothelial tissue affected by PH, miR-210 was elevated accompanied by decreased ISCU1/2 and Fe-S integrity. In mice, miR-210 repressed ISCU1/2 and promoted PH. Mice deficient in miR-210, via genetic/pharmacologic means or via an endothelial-specific manner, displayed increased ISCU1/2 and were resistant to Fe-S-dependent pathophenotypes and PH. Similar to hypoxia or miR-210 overexpression, ISCU1/2 knockdown also promoted PH. Finally, cardiopulmonary exercise testing of a woman with homozygous ISCU mutations revealed exercise-induced pulmonary vascular dysfunction. Thus, driven by acquired (hypoxia) or genetic causes, the miR-210-ISCU1/2 regulatory axis is a pathogenic lynchpin causing Fe-S deficiency and PH. These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings.
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DOI：
10.1016/j.bbamcr.2014.06.012
发表时间：
2014-11
影响因子：
5.1
作者：
Hale, Andrew;Lee, Changjin;Annis, Sofia;Min, Pil-Ki;Pande, Reena;Creager, Mark A.;Julian, Colleen G.;Moore, Lorna G.;Mitsialis, S. Alex;Hwang, Sarah J.;Kourembanas, Stella;Chan, Stephen Y.
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影响因子：
4.2
作者：
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Stormon, MO
DOI：
10.1152/ajpregu.00001.2011
发表时间：
2011-10-01
影响因子：
2.8
作者：
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通讯作者：
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影响因子：
1.7
作者：
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通讯作者：
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影响因子：
6
作者：
Fijalkowska, Iwona;Xu, Weiling;Tuder, Rubin M.
通讯作者：
Tuder, Rubin M.