Phospholamban Is Downregulated by pVHL-Mediated Degradation through Oxidative Stress in Failing Heart.
Phospholamban Is Downregulated by pVHL-Mediated Degradation through Oxidative Stress in Failing Heart.
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DOI：
10.3390/ijms18112232
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发表时间：
2017-10-25
影响因子：
5.6
通讯作者：
Asahi M
中科院分区：
文献类型：
--
作者：
Yokoe S;Asahi M
E3泛素连接酶von Hippel-Lindau（VHL）通过多聚泛素化调节蛋白质表达。虽然VHL蛋白（pVHL）被报道参与心脏功能，但其潜在机制尚不清楚。在这里，我们表明，pVHL上调两种类型的遗传扩张型心肌病（DCM）小鼠模型的心脏。与野生型小鼠相比，两种DCM小鼠模型均显示受磷蛋白（PLN）（肌浆网Ca 2 +-ATP酶的有效抑制剂）的表达显著降低，并且pVHL和PLN之间的相互作用增强。为了阐明pVHL是否参与衰竭心脏中PLN的降解，我们使用羰基氰化物间氯苯腙（CCCP），一种线粒体膜电位（MMP）降低试剂，来模拟表达PLN的HEK 293细胞中的心力衰竭状况，发现CCCP处理导致PLN降解并增加PLN和pVHL之间的相互作用。然而，这些效果被逆转与添加N-乙酰基-L-半胱氨酸。此外，HEK 293细胞中VHL和PLN的共转染降低了氧化应激下的PLN表达，而VHL的敲低增加了正常和氧化应激条件下的PLN表达。总之，我们提出，氧化应激上调pVHL表达，诱导PLN降解衰竭的心脏。
The E3 ubiquitin ligase, von Hippel–Lindau (VHL), regulates protein expression by polyubiquitination. Although the protein VHL (pVHL) was reported to be involved in the heart function, the underlying mechanism is unclear. Here, we show that pVHL was upregulated in hearts from two types of genetically dilated cardiomyopathy (DCM) mice models. In comparison with the wild-type mouse, both DCM mice models showed a significant reduction in the expression of phospholamban (PLN), a potent inhibitor of sarco(endo)plasmic reticulum Ca2+-ATPase, and enhanced interaction between pVHL and PLN. To clarify whether pVHL is involved in PLN degradation in failing hearts, we used carbonylcyanide m-chlorophenylhydrazone (CCCP), a mitochondrial membrane potential (MMP)-lowering reagent, to mimic the heart failure condition in PLN-expressing HEK293 cells and found that CCCP treatment resulted in PLN degradation and increased interaction between PLN and pVHL. However, these effects were reversed with the addition of N-acetyl-l-cysteine. Furthermore, the co-transfection of VHL and PLN in HEK293 cells decreased PLN expression under oxidative stress, whereas knockdown of VHL increased PLN expression both under normal and oxidative stress conditions. Together, we propose that oxidative stress upregulates pVHL expression to induce PLN degradation in failing hearts.
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