Synergistic induction of miR-126 by hypoxia and HDAC inhibitors in cardiac myocytes.
Synergistic induction of miR-126 by hypoxia and HDAC inhibitors in cardiac myocytes.
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DOI：
10.1016/j.bbrc.2012.11.061
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发表时间：
2013-01-11
影响因子：
3.1
通讯作者：
Wei, Jianqin
中科院分区：
文献类型：
--
作者：
Shi, Huaping;Chen, Lei;Wang, Huilan;Zhu, Shoukang;Dong, Chunming;Webster, Keith A.;Wei, Jianqin
HDAC抑制剂正在临床开发中，用于治疗肥厚型心肌病和心力衰竭，尽管其保护机制尚不完全清楚。Micro-RNA 126是一种内皮特异性miR，通过激活存活激酶ERK 1/2和Akt并增加促血管生成信号而在心脏中发挥重要的发育作用。在这里，我们提供了缺氧和HDAC抑制剂选择性和协同刺激心肌细胞中miR-126表达的第一个证据。在低氧暴露1小时后，miR-126表达增加1.7倍（p <0.05），并且通过用泛HDAC抑制剂Tricostatin A（TSA）同时阻断HDAC，miR-126表达进一步增强至3.0倍（p <0.01）。TSA单独不增加miR-126。同时，缺氧和TSA协同增加p-ERK和p-Akt而不影响VEGF-A水平。用si-RNA敲低miR-126消除了缺氧对p-ERK和p-Akt的诱导，而miR-126过表达模拟缺氧并与miR-126平行扩增p-ERK和p-Akt。结果表明，miR-126是HAT/HDAC的缺氧诱导靶点，其在心肌细胞中的激活可能通过在缺血期间选择性地激活细胞存活和促血管生成途径而有助于心脏保护。
HDAC inhibitors are under clinical development for the treatment of hypertrophic cardiomyopathy and heart failure although the mechanisms of protection are incompletely understood. Micro-RNA 126, an endothelium-specific miR has been assigned essential developmental roles in the heart by activating survival kinases ERK1/2 and Akt and increasing pro-angiogenic signaling. Here we provide the first evidence that hypoxia and HDAC inhibitors selectively and synergistically stimulate expression of miR-126 in cardiac myocytes. MiR-126 expression was increased 1.7-fold (p< 0.05) after 1h of hypoxic exposure and this was further enhanced to 3.0-fold (p<0.01) by simultaneously blocking HDAC with the pan-HDAC inhibitor Tricostatin A (TSA). TSA alone did not increase miR-126. In parallel, hypoxia and TSA synergistically increased p-ERK and p-Akt without effecting VEGF-A level. Knockdown of miR-126 with si-RNA eliminated inductions of p-ERK and p-Akt by hypoxia, whereas miR-126 overexpression mimicked hypoxia and amplified p-ERK and p-Akt in parallel with miR-126. The results suggest that miR-126 is a hypoxia-inducible target of HAT/HDAC and its activation in cardiac myocytes may contribute to cardioprotection by activating cell survival and proangiogenic pathways selectively during ischemia.
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影响因子：
14.8
作者：
Bradner, James E.;West, Nathan;Grachan, Melissa L.;Greenberg, Edward F.;Haggarty, Stephen J.;Warnow, Tandy;Mazitschek, Ralph
通讯作者：
Mazitschek, Ralph
DOI：
10.1161/hypertensionaha.108.125088
发表时间：
2009-03
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Glenn DJ;Wang F;Chen S;Nishimoto M;Gardner DG
通讯作者：
Gardner DG
影响因子：
3
作者：
Salloum FN;Yin C;Kukreja RC
通讯作者：
Kukreja RC
影响因子：
7.3
作者：
Iyer, Abishek;Fenning, Andrew;Brown, Lindsay
通讯作者：
Brown, Lindsay
影响因子：
15.9
作者：
Backs, Johannes;Song, Kunhua;Olson, Eric N.
通讯作者：
Olson, Eric N.