Cardiac Specific Overexpression of Mitochondrial Omi/HtrA2 Induces Myocardial Apoptosis and Cardiac Dysfunction.
Cardiac Specific Overexpression of Mitochondrial Omi/HtrA2 Induces Myocardial Apoptosis and Cardiac Dysfunction.
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线粒体 Omi/HtrA2 的心脏特异性过度表达可诱导心肌细胞凋亡和心脏功能障碍。
DOI：
10.1038/srep37927
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发表时间：
2016-12-07
影响因子：
4.6
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Wang K;Yuan Y;Liu X;Lau WB;Zuo L;Wang X;Ma L;Jiao K;Shang J;Wang W;Ma X;Liu H
心肌细胞凋亡是导致缺血性心脏病的一个重要问题。我们以前报道过胞浆内Omi/HtrA2的表达显著增加，触发心肌细胞的凋亡。然而，线粒体内Omi/HtrA2的增加是否会影响在体心肌存活尚不清楚。我们的目的是观察线粒体特异性的Omi/HtrA2对心肌细胞凋亡和心功能的影响。获得了过表达心脏特异性线粒体Omi/HtrA2的转基因小鼠，它们增加了心肌细胞凋亡，降低了收缩和舒张功能，并减少了左室重构。线粒体Omi/HtrA2在H9C2细胞中的瞬时或稳定过表达可促进细胞凋亡，caspase-3、-9活性和TUNEL染色均升高，这一作用可被特异性Omi/HtrA2抑制剂UCF-101完全阻断。机制研究表明，线粒体Omi/HtrA2过表达可降解线粒体抗凋亡蛋白HAX-1，这种作用可被UCF-101减弱。此外，过表达线粒体Omi/HtrA2的细胞对缺氧/复氧(H/R)诱导的细胞凋亡更加敏感。线粒体通透性转换抑制剂环孢素A(CsA)可阻断Omi/HtrA2从线粒体到细胞质的转位，并对缺氧/复氧诱导的caspase-3激活有不完全的保护作用。我们在体外和体内报道了线粒体Omi/HtrA2的过表达诱导心肌细胞凋亡和功能障碍。因此，直接抑制Omi/HtrA2或其线粒体胞浆易位的策略可能对心脏损伤具有保护作用。
Myocardial apoptosis is a significant problem underlying ischemic heart disease. We previously reported significantly elevated expression of cytoplasmic Omi/HtrA2, triggers cardiomyocytes apoptosis. However, whether increased Omi/HtrA2 within mitochondria itself influences myocardial survival in vivo is unknown. We aim to observe the effects of mitochondria-specific, not cytoplasmic, Omi/HtrA2 on myocardial apoptosis and cardiac function. Transgenic mice overexpressing cardiac-specific mitochondrial Omi/HtrA2 were generated and they had increased myocardial apoptosis, decreased systolic and diastolic function, and decreased left ventricular remodeling. Transiently or stably overexpression of mitochondria Omi/HtrA2 in H9C2 cells enhance apoptosis as evidenced by elevated caspase-3, -9 activity and TUNEL staining, which was completely blocked by Ucf-101, a specific Omi/HtrA2 inhibitor. Mechanistic studies revealed mitochondrial Omi/HtrA2 overexpression degraded the mitochondrial anti-apoptotic protein HAX-1, an effect attenuated by Ucf-101. Additionally, transfected cells overexpressing mitochondrial Omi/HtrA2 were more sensitive to hypoxia and reoxygenation (H/R) induced apoptosis. Cyclosporine A (CsA), a mitochondrial permeability transition inhibitor, blocked translocation of Omi/HtrA2 from mitochondrial to cytoplasm, and protected transfected cells incompletely against H/R-induced caspase-3 activation. We report in vitro and in vivo overexpression of mitochondrial Omi/HtrA2 induces cardiac apoptosis and dysfunction. Thus, strategies to directly inhibit Omi/HtrA2 or its cytosolic translocation from mitochondria may protect against heart injury.
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DOI：
10.1161/circoutcomes.109.910711
发表时间：
2010-05
期刊：
Circulation. Cardiovascular quality and outcomes
影响因子：
--
作者：
Moran A;Gu D;Zhao D;Coxson P;Wang YC;Chen CS;Liu J;Cheng J;Bibbins-Domingo K;Shen YM;He J;Goldman L
通讯作者：
Goldman L
影响因子：
3.8
作者：
Liu, Qi-bing;Liu, Lu-lu;Lou, Yi-jia
通讯作者：
Lou, Yi-jia
线粒体质量控制：有关帕金森氏病与pink1，Parkin和Omi/Htra2相关的见解，以保持线粒体稳态。
影响因子：
3
作者：
Dagda, Ruben K.;Chu, Charleen T.
通讯作者：
Chu, Charleen T.
影响因子：
4.8
作者：
Koontz, Jason;Kontrogianni-Konstantopoulos, Aikaterini
通讯作者：
Kontrogianni-Konstantopoulos, Aikaterini
影响因子：
5.1
作者：
Lucotte, Berangere;Tajhizi, Mehdi;Behbahani, Homira
通讯作者：
Behbahani, Homira