VDAC1蛋白的调控有助于长托宁对缺血-再灌注心肌的保护作用
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Regulation of VDAC1 contributes to the cardioprotective effects of penehyclidine hydrochloride during myocardial ischemia/reperfusion
背景与目的：长托宁（PHC）预处理可减轻心肌缺血/再灌注（I/R）损伤并抑制电压依赖性阴离子通道蛋白1（VDAC1）的表达。
1
方法：为了验证VDAC1在PHC介导的心肌I/R损伤中的保护作用，在PHC预处理和心肌I/R之前，将VDAC1表达构建体通过慢病毒转染至大鼠左心室心肌细胞中。
结果：VDAC1的过度表达加剧了I/R后的心脏功能障碍和心肌损伤，并且在I/R损伤期间PHC的心脏保护作用受抑制；此外，I/R心肌的VDAC1过度表达进一步增加细胞色素C从线粒体释放到细胞质，从而增加了半胱氨酸蛋白酶-3和Bax的表达水平、降低Bcl-2的表达水平；与单独I/R相比，PHC可抑制VDAC1过表达的心肌I/R期间线粒体依赖性细胞的凋亡，此外，经过PHC的预处理，缺氧/复氧（A /R）的H9c2心肌细胞VDAC1过度表达受抑制。体外实验结果进一步表明，VDAC1的过表达降低了A/R后H9c2细胞线粒体膜电位，线粒体膜通透性增加以及线粒体依赖性细胞的凋亡增加，并且VDAC1过表达抑制了PHC对A/ R期间线粒体功能和完整性的保护作用。
结论：心肌I/R期间，VDAC1的外源性过表达会抑制PHC的心肌保护作用，这可能与PHC抑制VDAC1的表达有关。
omao Lin, Boqun Cui, Jiayue Ren, Jun Ma；
Regulation of VDAC1 contributes to the cardioprotective effects of penehyclidine hydrochloride during myocardial ischemia/reperfusion；
Experimental Cell Research, https://doi.org/10.1016/j.yexcr.2018.04.004
BACKGROUND:Penehyclidine hydrochloride (PHC) preconditioning can alleviate myocardial ischemia/reperfusion (I/R) injury and inhibits the upregulation of voltage-dependent anion channel 1 (VDAC1) during I/R.
METHODS:To validate that VDAC1 is a bona fide target of PHC for the protection against myocardial I/R injury, VDAC1 expression construct was delivered by lentiviruses into rat left ventricular myocardium before PHC preconditioning and myocardial I/R.
RESULTS:Overexpression of VDAC1 exacerbated cardiac dysfunction and myocardial injury following I/R, and abolished the cardioprotective effect of PHC during I/R injury. Moreover, VDAC1 overexpression with myocardial I/R further increased cytochrome c release from mitochondria to cytoplasm, elevated the levels of cleaved caspase-3 and Bax, and decreased the level of Bcl-2 as compared with I/R alone, and PHC-mediated inhibition of mitochondria-dependent apoptosis during myocardial I/R was abolished by VDAC1 overexpression. In addition, VDAC1 was overexpressed in H9c2 cardiomyocytes undergoing anoxia/reoxygenation (A/R) with or without PHC pretreatment. The in vitro results showed that overexpression of VDAC1 further reduced mitochondrial membrane potential, increased mitochondrial membrane permeability and enhanced mitochondria-dependent apoptosis in H9c2 cells after A/R, and VDAC1 overexpression abrogated the protective effect of PHC on the mitochondrial function and integrity during A/R.
CONCLUSIONS:In conclusion, exogenous overexpression of VDAC1 during myocardial I/R inhibits the cardioprotective effects of PHC. These effects may be associated with the suppression of VDAC1 expression
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