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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2015

Open Access 01-12-2015 | Research

MicroRNA regulation of unfolded protein response transcription factor XBP1 in the progression of cardiac hypertrophy and heart failure in vivo

Authors: Quanlu Duan, Chen Chen, Lei Yang, Ni Li, Wei Gong, Sheng Li, Dao Wen Wang

Published in: Journal of Translational Medicine | Issue 1/2015

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Abstract

Background

XBP1 is a key transcription factor of the unfolded protein response in mammalian cells, which is involved in several cardiovascular pathological progression including cardiac hypertrophy and myocardial infarction, but its expression trend, function and upstream regulate mechanism in the development of heart failure are unclear. In the present study, therefore, the potential role of miRNAs in the regulation of XBP1 expression in heart failure was examined.

Methods and results

First, western blots showed that cardiac expression of ER stress marker XBP1 were induced in the early adaptive phase, but decreased in the maladaptive phase in hypertrophic and failing heart, while there was no obvious change of upstream ATF6 and IRE1 activity in this progression. Interestingly, we further found that XBP1 and its downstream target VEGF were attenuated by miR-30* and miR-214 in cardiomyocyte. Moreover, we found that miR-30* was significantly reduced in the early phase of cardiac hypertrophic animal model and in human failing hearts, while both miR-214 and miR-30* were increased in the maladaptive diseased heart, thereby contribute to impairment of cardiac XBP1 and VEGF expression.

Conclusions

These results provide the first clear link between miRNAs and direct regulation of XBP1 in heart failure and reveal that miR-214 and miR-30* synergistically regulates cardiac VEGF expression and angiogenesis by targeting XBP1 in the progression from adaptive hypertrophy to heart failure.
Appendix
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Literature
1.
2.
Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107:881–91.CrossRefPubMed
3.
Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13:89–102.PubMed
4.
Koong AC, Chauhan V, Romero-Ramirez L. Targeting XBP-1 as a novel anti-cancer strategy. Cancer Biol Ther. 2006;5:756–9.CrossRefPubMed
5.
6.
Lee J, Sun C, Zhou Y, Gokalp D, Herrema H, Park SW, Davis RJ, Ozcan U. p38 MAPK-mediated regulation of Xbp1 s is crucial for glucose homeostasis. Nat Med. 2011;17:1251–60.PubMedCentralCrossRefPubMed
7.
Park SW, Zhou Y, Lee J, Lu A, Sun C, Chung J, Ueki K, Ozcan U. The regulatory subunits of PI3 K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation. Nat Med. 2010;16:429–37.PubMedCentralCrossRefPubMed
8.
Zhou Y, Lee J, Reno CM, Sun C, Park SW, Chung J, Fisher SJ, White MF, Biddinger SB, Ozcan U. Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction. Nat Med. 2011;17:356–65.PubMedCentralCrossRefPubMed
9.
10.
So JS, Hur KY, Tarrio M, Ruda V, Frank-Kamenetsky M, Fitzgerald K, Koteliansky V, Lichtman AH, Iwawaki T, Glimcher LH, Lee AH. Silencing of lipid metabolism genes through IRE1alpha-mediated mRNA decay lowers plasma lipids in mice. Cell Metab. 2012;16:487–99.PubMedCentralCrossRefPubMed
11.
Wang S, Chen Z, Lam V, Han J, Hassler J, Finck BN, Davidson NO, Kaufman RJ. IRE1alpha-XBP1 s induces PDI expression to increase MTP activity for hepatic VLDL assembly and lipid homeostasis. Cell Metab. 2012;16:473–86.PubMedCentralCrossRefPubMed
12.
Margariti A, Li H, Chen T, Martin D, Vizcay-Barrena G, Alam S, Karamariti E, Xiao Q, Zampetaki A, Zhang Z, et al. XBP1 mRNA splicing triggers an autophagic response in endothelial cells through BECLIN-1 transcriptional activation. J Biol Chem. 2013;288:859–72.PubMedCentralCrossRefPubMed
13.
Zeng L, Xiao Q, Chen M, Margariti A, Martin D, Ivetic A, Xu H, Mason J, Wang W, Cockerill G, et al. Vascular endothelial cell growth-activated XBP1 splicing in endothelial cells is crucial for angiogenesis. Circulation. 2013;127:1712–22.CrossRefPubMed
14.
Wang ZV, Deng Y, Gao N, Pedrozo Z, Li DL, Morales CR, Criollo A, Luo X, Tan W, Jiang N, et al. Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway. Cell. 2014;156:1179–92.PubMedCentralCrossRefPubMed
15.
Duan Q, Yang L, Gong W, Chaugai S, Wang F, Chen C, Wang P, Zou MH, Wang DW. MicroRNA-214 is Up-Regulated in Heart Failure Patients and Suppresses XBP1-Mediated Endothelial Cells Angiogenesis. J Cell Physiol. 2015;230(8):1964–73.CrossRefPubMed
16.
Okada K, Minamino T, Tsukamoto Y, Liao Y, Tsukamoto O, Takashima S, Hirata A, Fujita M, Nagamachi Y, Nakatani T, et al. Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation. 2004;110:705–12.CrossRefPubMed
17.
Thuerauf DJ, Marcinko M, Gude N, Rubio M, Sussman MA, Glembotski CC. Activation of the unfolded protein response in infarcted mouse heart and hypoxic cultured cardiac myocytes. Circ Res. 2006;99:275–82.CrossRefPubMed
18.
Fu HY, Okada K, Liao Y, Tsukamoto O, Isomura T, Asai M, Sawada T, Okuda K, Asano Y, Sanada S, et al. Ablation of C/EBP homologous protein attenuates endoplasmic reticulum-mediated apoptosis and cardiac dysfunction induced by pressure overload. Circulation. 2010;122:361–9.CrossRefPubMed
19.
20.
Winter J, Jung S, Keller S, Gregory RI, Diederichs S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol. 2009;11:228–34.CrossRefPubMed
21.
22.
Sayed D, Hong C, Chen IY, Lypowy J, Abdellatif M. MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ Res. 2007;100:416–24.CrossRefPubMed
23.
24.
Ni L, Zhou C, Duan Q, Lv J, Fu X, Xia Y, Wang DW. β-AR blockers suppresses ER stress in cardiac hypertrophy and heart failure. PLoS ONE. 2011;6:e27294.PubMedCentralCrossRefPubMed
25.
26.
Duan Q, Wang X, Gong W, Ni L, Chen C, He X, Chen F, Yang L, Wang P, Wang DW. ER stress negatively modulates the expression of the miR-199a/214 cluster to regulates tumor survival and progression in human hepatocellular cancer. PLoS ONE. 2012;7:e31518.PubMedCentralCrossRefPubMed
27.
Ghosh R, Lipson KL, Sargent KE, Mercurio AM, Hunt JS, Ron D, Urano F. Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PLoS ONE. 2010;5:e9575.PubMedCentralCrossRefPubMed
28.
Pereira ER, Liao N, Neale GA, Hendershot LM. Transcriptional and post-transcriptional regulation of proangiogenic factors by the unfolded protein response. PLoS ONE. 2010;5:e12521.PubMedCentralCrossRefPubMed
29.
Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol. 2003;23:7448–59.PubMedCentralCrossRefPubMed
30.
Izumiya Y, Shiojima I, Sato K, Sawyer DB, Colucci WS, Walsh K. Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload. Hypertension. 2006;47:887–93.PubMedCentralCrossRefPubMed
31.
van Rooij E, Sutherland LB, Liu N, Williams AH, McAnally J, Gerard RD, Richardson JA, Olson EN. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci U S A. 2006;103:18255–60.PubMedCentralCrossRefPubMed
32.
van Rooij E, Sutherland LB, Thatcher JE, DiMaio JM, Naseem RH, Marshall WS, Hill JA, Olson EN. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci U S A. 2008;105:13027–32.PubMedCentralCrossRefPubMed
33.
Hullinger TG, Montgomery RL, Seto AG, Dickinson BA, Semus HM, Lynch JM, Dalby CM, Robinson K, Stack C, Latimer PA, et al. Inhibition of miR-15 protects against cardiac ischemic injury. Circ Res. 2012;110:71–81.PubMedCentralCrossRefPubMed
34.
Godwin JG, Ge X, Stephan K, Jurisch A, Tullius SG, Iacomini J. Identification of a microRNA signature of renal ischemia reperfusion injury. Proc Natl Acad Sci U S A. 2010;107:14339–44.PubMedCentralCrossRefPubMed
35.
Denby L, Ramdas V, McBride MW, Wang J, Robinson H, McClure J, Crawford W, Lu R, Hillyard DZ, Khanin R, et al. miR-21 and miR-214 are consistently modulated during renal injury in rodent models. Am J Pathol. 2011;179:661–72.PubMedCentralCrossRefPubMed
36.
el Azzouzi H, Leptidis S, Dirkx E, Hoeks J, van Bree B, Brand K, McClellan EA, Poels E, Sluimer JC, van den Hoogenhof MM, et al. The hypoxia-inducible microRNA cluster miR-199a approximately 214 targets myocardial PPARdelta and impairs mitochondrial fatty acid oxidation. Cell Metab. 2013;18:341–54.CrossRefPubMed
37.
Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 2006;20:515–24.CrossRefPubMed
38.
Kedde M, van Kouwenhove M, Zwart W. Oude Vrielink JA, Elkon R, Agami R: a Pumilio-induced RNA structure switch in p27-3′ UTR controls miR-221 and miR-222 accessibility. Nat Cell Biol. 2010;12:1014–20.CrossRefPubMed
39.
Byrd AE, Aragon IV, Brewer JW. MicroRNA-30c-2* limits expression of proadaptive factor XBP1 in the unfolded protein response. J Cell Biol. 2012;196:689–98.PubMedCentralCrossRefPubMed
40.
Matkovich SJ, Van Booven DJ, Youker KA, Torre-Amione G, Diwan A, Eschenbacher WH, Dorn LE, Watson MA, Margulies KB, Dorn GW 2nd. Reciprocal regulation of myocardial microRNAs and messenger RNA in human cardiomyopathy and reversal of the microRNA signature by biomechanical support. Circulation. 2009;119:1263–71.PubMedCentralCrossRefPubMed
41.
Reddy S, Zhao M, Hu DQ, Fajardo G, Hu S, Ghosh Z, Rajagopalan V, Wu JC, Bernstein D. Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure. Physiol Genomics. 2012;44:562–75.PubMedCentralCrossRefPubMed
42.
Volkmann I, Kumarswamy R, Pfaff N, Fiedler J, Dangwal S, Holzmann A, Batkai S, Geffers R, Lother A, Hein L, Thum T. MicroRNA-Mediated Epigenetic Silencing of Sirtuin1 Contributes to Impaired Angiogenic Responses. Circ Res. 2013;113:997–1003.CrossRefPubMed
43.
Miyagi H, Kanemoto S, Saito A, Asada R, Iwamoto H, Izumi S, Kido M, Gomi F, Nishida K, Kiuchi Y, Imaizumi K. Transcriptional regulation of VEGFA by the endoplasmic reticulum stress transducer OASIS in ARPE-19 cells. PLoS ONE. 2013;8:e55155.PubMedCentralCrossRefPubMed
44.
Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306:457–61.CrossRefPubMed
45.
Shao M, Shan B, Liu Y, Deng Y, Yan C, Wu Y, Mao T, Qiu Y, Zhou Y, Jiang S, et al. Hepatic IRE1alpha regulates fasting-induced metabolic adaptive programs through the XBP1s-PPARalpha axis signalling. Nat Commun. 2014;5:3528.PubMed
46.
Martinon F, Chen X, Lee AH, Glimcher LH. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol. 2010;11:411–8.PubMedCentralCrossRefPubMed
47.
Romero-Ramirez L, Cao H, Nelson D, Hammond E, Lee AH, Yoshida H, Mori K, Glimcher LH, Denko NC, Giaccia AJ, et al. XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res. 2004;64:5943–7.CrossRefPubMed
Metadata
Title
MicroRNA regulation of unfolded protein response transcription factor XBP1 in the progression of cardiac hypertrophy and heart failure in vivo
Authors
Quanlu Duan
Chen Chen
Lei Yang
Ni Li
Wei Gong
Sheng Li
Dao Wen Wang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2015
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-015-0725-4

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