miR-499 protects cardiomyocytes from H 2O 2-induced apoptosis via its effects on Pdcd4 and Pacs2.
miR-499 protects cardiomyocytes from H 2O 2-induced apoptosis via its effects on Pdcd4 and Pacs2.
复制标题
miR-499 通过影响 Pdcd4 和 Pacs2 保护心肌细胞免受 H2O2 诱导的细胞凋亡
作者：
Wang J;Jia Z;Zhang C;Sun M;Wang W;Chen P;Ma K;Zhang Y;Li X;Zhou C
背景microRNAs（miRNAs）是一类小的、非编码的内源性RNA，其在转录后调节一些蛋白质编码基因。miRNA在许多心脏病理生理过程中发挥重要作用，包括心肌梗死、心肌肥大和心力衰竭。miR-499在骨骼肌和心脏细胞中特异性表达，在心脏发育中受到差异调节和发挥作用。然而，miR-499在成熟心脏中的功能知之甚少。结果心肌组织中富含的miR-499对H2 O2诱导的心肌细胞凋亡具有保护作用。miR-499水平升高有利于生存，而miR-499水平降低有利于细胞凋亡。我们确定了三个促凋亡蛋白编码基因-Pdcd 4，Pacs 2和Dyrk 2-作为miR-499的靶点。miR-499通过抑制Pdcd 4和Pacs 2表达抑制心肌细胞凋亡，从而阻断Bid表达和BID线粒体易位。我们还发现H2 O2诱导的c-Jun磷酸化通过磷酸化的c-Jun与Myh 7 b启动子的结合在转录上上调miR-499的表达。结论miR-499对H2 O2诱导的心肌细胞线粒体凋亡具有抑制作用，对H2 O2诱导的心肌细胞损伤具有保护作用。
Background microRNAs (miRNAs) are a class of small, non-coding endogenous RNAs that post-transcriptionally regulate some protein-coding genes. miRNAs play an important role in many cardiac pathophysiological processes, including myocardial infarction, cardiac hypertrophy, and heart failure. miR-499, specifically expressed in skeletal muscle and cardiac cells, is differentially regulated and functions in heart development. However, the function of miR-499 in mature heart is poorly understood. Results We report that cardiac-abundant miR-499 could protect neonatal rat cardiomyocytes against H2O2-induced apoptosis. Increased miR-499 level favored survival, while decreased miR-499 level favored apoptosis. We identified three proapoptotic protein-coding genes—Pdcd4, Pacs2, and Dyrk2—as targets of miR-499. miR-499 inhibited cardiomyocyte apoptosis through its suppressive effect on Pdcd4 and Pacs2 expression, thereby blocking Bid expression and BID mitochondrial translocation. We also found that H2O2-induced phosphorylation of c-Jun transcriptionally upregulated miR-499 expression via binding of phosphorylated c-Jun to the Myh7b promoter. Conclusions Our results revealed that miR-499 played an inhibiting role in the mitochondrial apoptosis pathway, and had protective effects against H2O2-induced injury in cardiomyocytes.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
3.7
作者：
Fu JD;Rushing SN;Lieu DK;Chan CW;Kong CW;Geng L;Wilson KD;Chiamvimonvat N;Boheler KR;Wu JC;Keller G;Hajjar RJ;Li RA
通讯作者：
Li RA
影响因子：
9.3
作者：
Adachi, Taichi;Nakanishi, Michio;Iwai, Naoharu
通讯作者：
Iwai, Naoharu
影响因子：
8
作者：
Noonan, E. J.;Place, R. F.;Dahiya, R.
通讯作者：
Dahiya, R.
影响因子：
14.9
作者：
Harris, MA;Clark, J;White, R
通讯作者：
White, R