lncRNA MIAT functions as a competing endogenous RNA to upregulate DAPK2 by sponging miR-22-3p in diabetic cardiomyopathy

Cell Death and Disease - Tập 8 Số 7 - Trang e2929-e2929
Xiang Zhou1, Wei Zhang1, Mengchao Jin1, Jianchang Chen1, Weiting Xu1, Xiangqing Kong2
1Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
2Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

Tóm tắt

AbstractWe previously established a rat model of diabetic cardiomyopathy (DCM) and found that the expression of long non-coding RNA myocardial infarction–associated transcript (MIAT) was significantly upregulated. The present study was aimed to determine the pathologic role of MIAT in the development of DCM. MIAT knockdown was found to reduce cardiomyocyte apoptosis and improve left ventricular function in diabetic rats. High glucose could increase MIAT expression and induce apoptosis in cultured neonatal cardiomyocytes. The results of luciferase reporter assay and RNA immunoprecipitation assay revealed that MIAT was targeted by miR-22-3p in an AGO2-dependent manner. In addition, the 3′-untranslated region of DAPK2 was fused to the luciferase coding region and transfected into HEK293 cells with miR-22-3p mimic, and the results showed that DAPK2 was a direct target of miR-22-3p. Our findings also indicated that MIAT overexpression could counteract the inhibitory effect of miR-22-3p on DAPK2. Moreover, MIAT knockdown was found to reduce DAPK2 expression and inhibit apoptosis in cardiomyocytes exposed to high glucose. In conclusion, our study demonstrates that MIAT may function as a competing endogenous RNA to upregulate DAPK2 expression by sponging miR-22-3p, which consequently leads to cardiomyocyte apoptosis involved in the pathogenesis of DCM.

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Tài liệu tham khảo

Aneja A, Tang WH, Bansilal S, Garcia MJ, Farkouh ME . Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options. Am J Med 2008; 121: 748–757.

Bugger H, Abel ED . Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 2014; 57: 660–671.

Moran VA, Perera RJ, Khalil AM . Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs. Nucleic Acids Res 2012; 40: 6391–6400.

I Ishii N, Ozaki K, Sato H, Mizuno H, Saito S, Takahashi A et al. Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction. J Hum Genet 2006; 51: 1087–1099.

Yan B, Yao J, Liu JY, Li XM, Wang XQ, Li YJ et al. lncRNA-MIAT regulates microvascular dysfunction by functioning as a competing endogenous RNA. Circ Res 2015; 116: 1143–1156.

Britschgi A, Trinh E, Rizzi M, Jenal M, Ress A, Tobler A et al. DAPK2 is a novel E2F1/KLF6 target gene involved in their proapoptotic function. Oncogene 2008; 27: 5706–5716.

Schlegel CR, Fonseca AV, Stöcker S, Georgiou ML, Misterek MB, Munro CE et al. DAPK2 is a novel modulator of TRAIL-induced apoptosis. Cell Death Differ 2014; 21: 1780–1791.

Vausort M, Wagner DR, Devaux Y . Long noncoding RNAs in patients with acute myocardial infarction. Circ Res 2014; 115: 668–677.

Shen Y, Dong LF, Zhou RM, Yao J, Song YC, Yang H et al. Role of long non-coding RNA MIAT in proliferation, apoptosis and migration of lens epithelial cells: a clinical and in vitro study. J Cell Mol Med 2016; 20: 537–548.

Aprea J, Prenninger S, Dori M, Ghosh T, Monasor LS, Wessendorf E et al. Transcriptome sequencing during mouse brain development identifies long non-coding RNAs functionally involved in neurogenic commitment. EMBO J 2013; 32: 3145–3160.

Crea F, Venalainen E, Ci X, Cheng H, Pikor L, Parolia A et al. The role of epigenetics and long noncoding RNA MIAT in neuroendocrine prostate cancer. Epigenomics 2016; 8: 721–731.

Ip JY, Sone M, Nashiki C, Pan Q, Kitaichi K, Yanaka K et al. Gomafu lncRNA knockout mice exhibit mild hyperactivity with enhanced responsiveness to the psychostimulant methamphetamine. Sci Rep 2016; 6: 27204.

Tay Y, Rinn J, Pandolfi PP . The multilayered complexity of ceRNA crosstalk and competition. Nature 2014; 505: 344–352.

Li X, Wang H, Yao B, Xu W, Chen J, Zhou X . lncRNA H19/miR-675 axis regulates cardiomyocyte apoptosis by targeting VDAC1 in diabetic cardiomyopathy. Sci Rep 2016; 6: 36340.

Zhang M, Gu H, Xu W, Zhou X . Down-regulation of lncRNA MALAT1 reduces cardiomyocyte apoptosis and improves left ventricular function in diabetic rats. Int J Cardiol 2016; 203: 214–216.

Zhou X, Feng Y, Zhan Z, Chen J . Hydrogen sulfide alleviates diabetic nephropathy in a streptozotocin-induced diabetic rat model. J Biol Chem 2014; 289: 28827–28834.

del Monte F, Hajjar RJ . Efficient viral gene transfer to rodent hearts in vivo. Methods Mol Biol 2003; 219: 179–193.

Zhou X, An G, Lu X . Hydrogen sulfide attenuates the development of diabetic cardiomyopathy. Clin Sci 2015; 128: 325–335.

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Cell Death and Disease

Tập 8 Số 7

e2929-e2929

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