gp-91 mediates histone deacetylase inhibition-induced cardioprotection.
gp-91 mediates histone deacetylase inhibition-induced cardioprotection.
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DOI：
10.1016/j.bbamcr.2010.04.007
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发表时间：
2010-07
期刊：
影响因子：
--
通讯作者：
Liu JT
中科院分区：
文献类型：
--
作者：
Zhao TC;Zhang LX;Cheng G;Liu JT
我们最近发现，组蛋白去乙酰化酶（HDAC）的抑制可保护心脏免受缺血和再灌注（I/R）损伤。HDAC抑制诱导心脏保护的机制仍不清楚。我们试图研究是否糖蛋白-91，NADPH氧化酶的亚基的遗传破坏，将减轻心脏保护HDAC抑制。野生型和gp-91−/−小鼠用HDAC的有效抑制剂，阿司他丁A（TSA，0.1mg/kg，i. p.）处理。24小时后，对灌注的心脏进行30分钟的缺血和30分钟的再灌注。HDAC抑制野生型小鼠心室功能恢复和梗死面积的减少产生显着的改善。TSA诱导的心脏保护作用随着gp 91基因缺失而消除。值得注意的是，蛋白质印迹和免疫染色显示HDAC抑制后心肌中gp-91显著增加，这导致随后活性氧（ROS）产生的轻度增加。TSA（50 nmol/L）预处理H9 c2成心肌细胞可减少细胞坏死，增加细胞存活率，而转染gp-91 siRNA可抑制细胞坏死，而转染scrambled siRNA则无此作用。此外，用TSA处理PLB-985 gp 91 +/+细胞增加了对SI的抗性，这也随着gp 91 phox缺陷PLB-985细胞中gp 91的遗传破坏而减弱。TSA处理抑制了暴露于SI的H9 c2成心肌细胞和PLB-985 gp 91 +/+细胞中活性caspase-3的增加，这通过siRNA敲低gp-91来阻止。这些结果表明，由gp-91和HDAC抑制组成的级联反应在协调心脏保护作用中起着重要作用。
We have recently shown that the inhibition of histone deacetylases (HDAC) protects the heart against ischemia and reperfusion (I/R) injury. The mechanism by which HDAC inhibition induces cardioprotection remains unknown. We sought to investigate whether the genetic disruption of gp-91, a subunit of NADPH-oxidase, would mitigate cardioprotection of HDAC inhibition. Wild-type and gp-91−/− mice were treated with a potent inhibitor of HDACs, trichostatin A (TSA, 0.1mg/kg, i.p.). Twenty-four hours later, the perfused hearts were subjected to 30 min of ischemia and 30 min of reperfusion. HDAC inhibition in wild-type mice produced marked improvements in ventricular functional recovery and the reduction of infarct size. TSA-induced cardioprotection was eliminated with genetic deletion of gp91. Notably, Western blot and immunostaining displayed a significant increase in gp-91 in myocardium following HDAC inhibition, which resulted in a mildly subsequent increase in the production of reactive oxygen species (ROS). The pretreatment of H9c2 cardiomyoblasts with TSA (50 nmol/L) decreased cell necrosis and increased viability in response to simulated ischemia (SI), which was abrogated by the transfection of cells with gp-91 siRNA, but not by scrambled siRNA. Furthermore, treatment of PLB-985 gp91+/+cells with TSA increased the resistance to SI, which also diminished with genetic disruption of gp91 in gp91phox-deficient PLB-985 cells. TSA treatment inhibited the increased active caspase-3 in H9c2 cardiomyoblasts and PLB-985 gp91+/+cells exposed to SI, which were prevented by knockdown of gp-91 by siRNA. These results suggest that a cascade consisting of gp-91 and HDAC inhibition plays an essential role in orchestrating the cardioprotective effect.
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影响因子：
64.8
作者：
Finnin, MS;Donigian, JR;Pavletich, NP
通讯作者：
Pavletich, NP
DOI：
10.1152/ajpregu.00783.2007
发表时间：
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影响因子：
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作者：
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作者：
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通讯作者：
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影响因子：
37.8
作者：
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通讯作者：
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