Identification of a NF-κB cardioprotective gene program: NF-κB regulation of Hsp70.1 contributes to cardioprotection after permanent coronary occlusion.
Identification of a NF-κB cardioprotective gene program: NF-κB regulation of Hsp70.1 contributes to cardioprotection after permanent coronary occlusion.
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DOI：
10.1016/j.yjmcc.2011.03.011
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发表时间：
2011-07
影响因子：
5
通讯作者：
Jones WK
中科院分区：
文献类型：
--
作者：
Wilhide ME;Tranter M;Ren X;Chen J;Sartor MA;Medvedovic M;Jones WK
转录因子核因子-κB在冠脉永久闭塞和晚期缺血预适应后具有心脏保护作用，但在心脏缺血/再灌注后具有细胞损伤作用。有关核因子-κB依赖的心脏保护作用的信息有限，而参与PO后心脏保护作用的核因子-κB依赖的基因也完全未知。该研究的目的是确定有助于PO后心脏保护的NF-κB依赖基因。利用基因芯片分析，通过确定PO调节的基因和由NF-κB调节的基因之间的重叠，来描绘可能有助于NF-κB依赖的心脏保护的基因，使用在心脏中遗传地消除了NF-κB激活的小鼠。这项分析确定了16个基因作为PO后NF-κB依赖效应的候选基因。这组基因与我们之前确定的在IPC后受NF-κB调控的基因集重叠，但与之显著不同。编码热休克蛋白70.3(Hspa1a)和热休克蛋白70.1(Hspa1b)的基因是PO后最显著的调控基因，并被NF-κB上调。结果在基因敲除小鼠的实验中，Hsp70.1有助于PO后依赖于NF-κB的心脏保护，并且可能至少部分地是依赖于NF-κB的心脏保护作用的基础。我们先前的研究结果表明，Hsp70.1在I/R损伤后具有一定的损伤作用。这表明，与NF-κB本身一样，HSP70.1对心肌存活具有相反的作用，提示这可能是不同的缺血刺激后，NF-κB具有相似的对抗作用的基础。这项研究的意义在于，了解缺血性损伤后由NF-κB调控的基因网络可能会导致识别更适合临床开发的治疗靶点。
The transcription factor Nuclear Factor Kappa B (NF-κB) has been shown to be cardioprotective after permanent coronary occlusion (PO) and late ischemic preconditioning (IPC), and yet it is cell injurious after ischemia/reperfusion (I/R) in the heart. There is limited information regarding NF-κB-dependent cardioprotection, and the NF-κB-dependent genes that contribute to the cardioprotection after PO are completely unknown. The objective of the study was to identify NF-κB-dependent genes that contribute to cardioprotection after PO. Microarray analysis was used to delineate genes that potentially contribute to the NF-κB-dependent cardioprotection by determining the overlap between the set of PO regulated genes and genes regulated by NF-κB, using mice with genetic abrogation of NF-κB activation in the heart. This analysis identified 16 genes as candidates for NF-κB-dependent effects after PO. This set of genes overlaps with, but is significantly different from the set of genes we previously identified as regulated by NF-κB after IPC. The genes encoding heat shock protein 70.3 (hspa1a) and heat shock protein 70.1 (hspa1b) were the most significantly regulated genes after PO and were up-regulated by NF-κB. Results using knockout mice show that Hsp70.1 contributes to NF-κB-dependent cardioprotection after PO and likely underlies, at least in part, the NF-κB-dependent cardioprotective effect. Our previous results show that Hsp70.1 is injurious after I/R injury. This demonstrates that, like NF-κB itself, Hsp70.1 has antithetical effects on myocardial survival and suggests that this may underlie the similar antithetical effects of NF-κB after different ischemic stimuli. The significance of the research is that understanding the gene network regulated by NF-κB after ischemic insult may lead to identification of therapeutic targets more appropriate for clinical development.
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DOI：
10.1152/ajpheart.00379.2005
发表时间：
2006-02-01
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Turco, M. C.
影响因子：
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作者：
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通讯作者：
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