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01-05-2013 | Original Contribution

NDRG2: a newly identified mediator of insulin cardioprotection against myocardial ischemia–reperfusion injury

Authors: Zhongchan Sun, Guang Tong, Nan Ma, Jianying Li, Xiujuan Li, Shuang Li, Jingyu Zhou, Lize Xiong, Feng Cao, Libo Yao, Haichang Wang, Lan Shen

Published in: Basic Research in Cardiology | Issue 3/2013

Abstract

The N-myc downstream-regulated gene 2 (NDRG2) is involved in cell apoptosis and survival. Although reported to be highly expressed in the cardiac tissue, the biological function of NDRG2 in the heart remains to be established. Insulin exerts protective effects against myocardial ischemia/reperfusion (I/R) injury through the PI3K/Akt pathway. Here, we examined the changes in phosphorylation of NDRG2, a novel substrate and phosphoprotein of Akt, in insulin-induced protection against myocardial I/R. Rat hearts were subjected to 30 min regional ischemia followed by reperfusion with or without insulin at the onset of reperfusion. Reperfusion with insulin inhibited myocardial apoptosis and reduced infarct size, as well as significantly up-regulated myocardial Akt and NDRG2 phosphorylation levels compared with the I/R group. These effects of insulin were blocked by pretreatment with the PI3K inhibitor wortmannin or Akt inhibitor. To further ascertain the role of NDRG2 in insulin-induced cardioprotection, cardiomyocytes were transduced with a lentivirus encoding shRNA targeting NDRG2 (loss-of-function), which rendered the cells more susceptible to I/R injury and significantly blunted the anti-apoptotic effect of insulin. Moreover, the NDRG2 shRNA lentivirus was tested in vivo, and NDRG2 knockdown aggravated myocardial I/R injury and attenuated the insulin-mediated cardioprotection against I/R injury. Taken together, these results suggest a novel role of PI3K/Akt/NDRG2 signaling in the cardioprotective effect of insulin.

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Boulkroun S, Fay M, Zennaro MC, Escoubet B, Jaisser F, Blot-Chabaud M, Farman N, Courtois-Coutry N (2002) Characterization of rat NDRG2 (N-Myc downstream regulated gene 2), a novel early mineralocorticoid-specific induced gene. J Biol Chem 277:31506–31515. doi:10.1074/jbc.M200272200 PubMedCrossRef

Boulkroun S, Le Moellic C, Blot-Chabaud M, Farman N, Courtois-Coutry N (2005) Expression of androgen receptor and androgen regulation of NDRG2 in the rat renal collecting duct. Pflugers Arch 451:388–394. doi:0.1007/s00424-005-1410-x PubMedCrossRef

Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868. doi:10.1016/S0092-8674(00)80595-4 PubMedCrossRef

Burchfield JG, Lennard AJ, Narasimhan S, Hughes WE, Wasinger VC, Corthals GL, Okuda T, Kondoh H, Biden TJ, Schmitz-Peiffer C (2004) Akt mediates insulin-stimulated phosphorylation of Ndrg2: evidence for cross-talk with protein kinase C theta. J Biol Chem 279:18623–18632. doi:10.1074/jbc.M401504200 PubMedCrossRef

Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321. doi:10.1126/science.282.5392.1318 PubMedCrossRef

Choi SC, Kim KD, Kim JT, Kim JW, Yoon DY, Choe YK, Chang YS, Paik SG, Lim JS (2003) Expression and regulation of NDRG2 (N-myc downstream regulated gene 2) during the differentiation of dendritic cells. FEBS Lett 553:413–418. doi:S0014579303010305 PubMedCrossRef

Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241. doi:10.1016/S0092-8674(00)80405-5 PubMedCrossRef

Del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G (1997) Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278:687–689. doi:10.1126/science.278.5338.687 PubMedCrossRef

Deng Y, Yao L, Chau L, Ng SS, Peng Y, Liu X, Au WS, Wang J, Li F, Ji S, Han H, Nie X, Li Q, Kung HF, Leung SY, Lin MC (2003) N-Myc downstream-regulated gene 2 (NDRG2) inhibits glioblastoma cell proliferation. Int J Cancer 106:342–347. doi:10.1002/ijc.11228 PubMedCrossRef

10.

Esumi K, Nishida M, Shaw D, Smith TW, Marsh JD (1991) NADH measurements in adult rat myocytes during simulated ischemia. Am J Physiol 260:H1743–H1752PubMed

11.

Foletta VC, Prior MJ, Stupka N, Carey K, Segal DH, Jones S, Swinton C, Martin S, Cameron-Smith D, Walder KR (2009) NDRG2, a novel regulator of myoblast proliferation, is regulated by anabolic and catabolic factors. J Physiol 587:1619–1634. doi:jphysiol.2008.167882 PubMedCrossRef

12.

Fuglesteg BN, Suleman N, Tiron C, Kanhema T, Lacerda L, Andreasen TV, Sack MN, Jonassen AK, Mjos OD, Opie LH, Lecour S (2008) Signal transducer and activator of transcription 3 is involved in the cardioprotective signalling pathway activated by insulin therapy at reperfusion. Basic Res Cardiol 103:444–453. doi:10.1007/s00395-008-0728-x PubMedCrossRef

13.

Gao F, Gao E, Yue TL, Ohlstein EH, Lopez BL, Christopher TA, Ma XL (2002) Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation. Circulation 105:1497–1502. doi:10.1161/01.CIR.0000012529.00367.0F PubMedCrossRef

14.

Ghaboura N, Tamareille S, Ducluzeau PH, Grimaud L, Loufrani L, Croue A, Tourmen Y, Henrion D, Furber A, Prunier F (2011) Diabetes mellitus abrogates erythropoietin-induced cardioprotection against ischemic-reperfusion injury by alteration of the RISK/GSK-3beta signaling. Basic Res Cardiol 106:147–162. doi:10.1007/s00395-010-0130-3 PubMedCrossRef

15.

Grace PA (1994) Ischaemia-reperfusion injury. Br J Surg 81:637–647PubMedCrossRef

16.

Grill CJ, Sivaprasad U, Cohick WS (2002) Constitutive expression of IGF-binding protein-3 by mammary epithelial cells alters signaling through Akt and p70S6 kinase. J Mol Endocrinol 29:153–162. doi:10.1677/jme.0.0290153 PubMedCrossRef

17.

Hausenloy DJ, Yellon DM (2004) New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res 61:448–460. doi:10.1016/j.cardiores.2003.09.024 PubMedCrossRef

18.

Heusch G (2013) Cardioprotection: chances and challenges of its translation to the clinic. Lancet 381:166–175. doi:10.1016/S0140-6736(12)60916-7 PubMedCrossRef

19.

Heusch G, Boengler K, Schulz R (2008) Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation 118:1915–1919. doi:10.1161/CIRCULATIONAHA.108.805242 PubMedCrossRef

20.

Heusch G, Musiolik J, Gedik N, Skyschally A (2011) Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circ Res 109:1302–1308. doi:10.1161/CIRCRESAHA.111.255604 PubMedCrossRef

21.

Hua Y, Zhang Y, Ceylan-Isik AF, Wold LE, Nunn JM, Ren J (2011) Chronic Akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: role of autophagy. Basic Res Cardiol 106:1173–1191. doi:10.1007/s00395-011-0222-8 PubMedCrossRef

22.

Klippel A, Kavanaugh WM, Pot D, Williams LT (1997) A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain. Mol Cell Biol 17:338–344PubMed

23.

Kohn AD, Takeuchi F, Roth RA (1996) Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. J Biol Chem 271:21920–21926PubMedCrossRef

24.

Lawlor MA, Alessi DR (2001) PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Sci 114:2903–2910PubMed

25.

Levkau B, Schafers M, Wohlschlaeger J, von Wnuck Lipinski K, Keul P, Hermann S, Kawaguchi N, Kirchhof P, Fabritz L, Stypmann J, Stegger L, Flogel U, Schrader J, Fischer JW, Hsieh P, Ou YL, Mehrhof F, Tiemann K, Ghanem A, Matus M, Neumann J, Heusch G, Schmid KW, Conway EM, Baba HA (2008) Survivin determines cardiac function by controlling total cardiomyocyte number. Circulation 117:1583–1593. doi:10.1161/CIRCULATIONAHA.107.734160 PubMedCrossRef

26.

Li J, Wu F, Zhang H, Fu F, Ji L, Dong L, Li Q, Liu W, Zhang Y, Lv A, Wang H, Ren J, Gao F (2009) Insulin inhibits leukocyte-endothelium adherence via an Akt-NO-dependent mechanism in myocardial ischemia/reperfusion. J Mol Cell Cardiol 47:512–519. doi:10.1016/j.yjmcc.2009.07.010 PubMedCrossRef

27.

Li J, Zhang H, Wu F, Nan Y, Ma H, Guo W, Wang H, Ren J, Das UN, Gao F (2008) Insulin inhibits tumor necrosis factor-alpha induction in myocardial ischemia/reperfusion: role of Akt and endothelial nitric oxide synthase phosphorylation. Crit Care Med 36:1551–1558. doi:10.1097/CCM.0b013e3181782335 PubMedCrossRef

28.

Li QX, Xiong ZY, Hu BP, Tian ZJ, Zhang HF, Gou WY, Wang HC, Gao F, Zhang QJ (2009) Aging-associated insulin resistance predisposes to hypertension and its reversal by exercise: the role of vascular vasorelaxation to insulin. Basic Res Cardiol 104:269–284. doi:10.1007/s00395-008-0754-8 PubMedCrossRef

29.

Li Y, Yang J, Li S, Zhang J, Zheng J, Hou W, Zhao H, Guo Y, Liu X, Dou K, Situ Z, Yao L (2011) N-myc downstream-regulated gene 2, a novel estrogen-targeted gene, is involved in the regulation of Na⁺/K⁺-ATPase. J Biol Chem 286:32289–32299. doi:10.1074/jbc.M111.247825 PubMedCrossRef

30.

Liu J, Zhang J, Wang X, Li Y, Chen Y, Li K, Yao L, Guo G (2010) HIF-1 and NDRG2 contribute to hypoxia-induced radioresistance of cervical cancer Hela cells. Exp Cell Res 316:1985–1993. doi:10.1016/j.yexcr.2010.02.028 PubMedCrossRef

31.

Liu S, Yang P, Kang H, Lu L, Zhang Y, Pan J, Rui YC (2010) NDRG2 induced by oxidized LDL in macrophages antagonizes growth factor productions via selectively inhibiting ERK activation. Biochim Biophys Acta 1801:106–113. doi:10.1016/j.bbalip.2009.09.022 PubMedCrossRef

32.

Lusis EA, Watson MA, Chicoine MR, Lyman M, Roerig P, Reifenberger G, Gutmann DH, Perry A (2005) Integrative genomic analysis identifies NDRG2 as a candidate tumor suppressor gene frequently inactivated in clinically aggressive meningioma. Cancer Res 65:7121–7126. doi:10.1158/0008-5472.CAN-05-0043 PubMedCrossRef

33.

Ma J, Jin H, Wang H, Yuan J, Bao T, Jiang X, Zhang W, Zhao H, Yao L (2008) Expression of NDRG2 in clear cell renal cell carcinoma. Biol Pharm Bull 31:1316–1320. doi:JST.JSTAGE/bpb/31.1316 PubMedCrossRef

34.

Murray JT, Campbell DG, Morrice N, Auld GC, Shpiro N, Marquez R, Peggie M, Bain J, Bloomberg GB, Grahammer F, Lang F, Wulff P, Kuhl D, Cohen P (2004) Exploitation of KESTREL to identify NDRG family members as physiological substrates for SGK1 and GSK3. Biochem J 384:477–488. doi:10.1042/BJ20041057 PubMedCrossRef

35.

Oh SS, Kim D, Kim DH, Chang HH, Sohn KC, Kim KH, Jung SH, Lee BK, Kim JH, Kim KD (2012) NDRG2 correlated with favorable recurrence-free survival inhibits metastasis of mouse breast cancer cells via attenuation of active TGF-beta production. Carcinogenesis 33:1882–1888. doi:10.1093/carcin/bgs211 PubMedCrossRef

36.

Philpott KL, McCarthy MJ, Klippel A, Rubin LL (1997) Activated phosphatidylinositol 3-kinase and Akt kinase promote survival of superior cervical neurons. J Cell Biol 139:809–815. doi:10.1083/jcb.139.3.809 PubMedCrossRef

37.

Shen L, Liu X, Hou W, Yang G, Wu Y, Zhang R, Li X, Che H, Lu Z, Zhang Y, Yao L (2010) NDRG2 is highly expressed in pancreatic beta cells and involved in protection against lipotoxicity. Cell Mol Life Sci 67:1371–1381. doi:10.1007/s00018-010-0258-1 PubMedCrossRef

38.

Si R, Tao L, Zhang HF, Yu QJ, Zhang R, Lv AL, Zhou N, Cao F, Guo WY, Ren J, Wang HC, Gao F (2011) Survivin: a novel player in insulin cardioprotection against myocardial ischemia/reperfusion injury. J Mol Cell Cardiol 50:16–24. doi:10.1016/j.yjmcc.2010.08.017 PubMedCrossRef

39.

Skyschally A, van Caster P, Boengler K, Gres P, Musiolik J, Schilawa D, Schulz R, Heusch G (2009) Ischemic postconditioning in pigs: no causal role for RISK activation. Circ Res 104:15–18. doi:10.1161/CIRCRESAHA.108.186429 PubMedCrossRef

40.

Skyschally A, van Caster P, Iliodromitis EK, Schulz R, Kremastinos DT, Heusch G (2009) Ischemic postconditioning: experimental models and protocol algorithms. Basic Res Cardiol 104:469–483. doi:10.1007/s00395-009-0040-4 PubMedCrossRef

41.

Sun Z, Shen L, Sun X, Tong G, Sun D, Han T, Yang G, Zhang J, Cao F, Yao L, Wang H (2011) Variation of NDRG2 and c-Myc expression in rat heart during the acute stage of ischemia/reperfusion injury. Histochem Cell Biol 135:27–35. doi:10.1007/s00418-010-0776-9 PubMedCrossRef

42.

Takahashi K, Saitoh A, Yamada M, Iwai T, Inagaki M, Yamada M (2012) Dexamethasone indirectly induces Ndrg2 expression in rat astrocytes. J Neurosci Res 90:160–166. doi:10.1002/jnr.22727 PubMedCrossRef

43.

Tao L, Gao E, Jiao X, Yuan Y, Li S, Christopher TA, Lopez BL, Koch W, Chan L, Goldstein BJ, Ma XL (2007) Adiponectin cardioprotection after myocardial ischemia/reperfusion involves the reduction of oxidative/nitrative stress. Circulation 115:1408–1416. doi:10.1161/CIRCULATIONAHA.106.666941 PubMedCrossRef

44.

Tong G, Sun Z, Wei X, Gu C, Kaye AD, Wang Y, Li J, Zhang Q, Guo H, Yu S, Yi D, Pei J (2011) U50,488H postconditioning reduces apoptosis after myocardial ischemia and reperfusion. Life Sci 88:31–38. doi:10.1016/j.lfs.2010.10.018 PubMedCrossRef

45.

Wang L, Liu N, Yao L, Li F, Zhang J, Deng Y, Liu J, Ji S, Yang A, Han H, Zhang Y, Han W, Liu X (2008) NDRG2 is a new HIF-1 target gene necessary for hypoxia-induced apoptosis in A549 cells. Cell Physiol Biochem 21:239–250. doi:10.1159/000113765 PubMedCrossRef

46.

Wang L, Liu N, Yao L, Li F, Zhang J, Deng Y, Liu J, Ji S, Yang A, Han H, Zhang Y, Zhang J, Han W, Liu X (2008) NDRG2 is a new HIF-1 target gene necessary for hypoxia-induced apoptosis in A549 cells. Cell Physiol Biochem 21:239–250. doi:10.1159/000113765 PubMedCrossRef

47.

Zhou RH, Kokame K, Tsukamoto Y, Yutani C, Kato H, Miyata T (2001) Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart. Genomics 73:86–97. doi:10.1006/geno.2000.6496 PubMedCrossRef

Title: NDRG2: a newly identified mediator of insulin cardioprotection against myocardial ischemia–reperfusion injury
Authors: Zhongchan Sun
Guang Tong
Nan Ma
Jianying Li
Xiujuan Li
Shuang Li
Jingyu Zhou
Lize Xiong
Feng Cao
Libo Yao
Haichang Wang
Lan Shen
Publication date: 01-05-2013
Publisher: Springer-Verlag
Published in: Basic Research in Cardiology / Issue 3/2013
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-013-0341-5

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NDRG2: a newly identified mediator of insulin cardioprotection against myocardial ischemia–reperfusion injury

Abstract

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Abstract

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