Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2016; 20: 3653-3660 LncRNA MIAT enhances cardiac hypertrophy partly through sponging miR-150
X.-H. ZHU 1, Y.-X. YUAN 2, S.-L. RAO 3, P. WANG 4
1VIP Ward, Zhumadian Central Hospital, Zhumadian, Henan, China 2Department of Cardiology, Zoucheng People’s Hospital, Zoucheng, Shandong, China 3Department of Emergency, Binzhou People’s Hospital, Binzhou, Shandong, China Shandong, China 4The 2 nd Department of Cardiology, Feicheng mining industry Central Hospital, Feicheng, Shandong, China Xiuhua Zhu and Yuxiang Yuan contribtued equally to this study
Abstract. – OBJECTIVE: In this work, we characterized by an enlargement of cardiomy - aimed to study whether myocardial infarction ocytes and the addition of contractile proteins 1,2 . associated transcript (MIAT) exerts a regulative Sustained cardiac hypertrophy and maladaptive effect on cardiac hypertrophy via acting as a cardiac remodeling significantly increased the risk miR-150 sponge. 3 MATERIALS AND METHODS: Cardiac hyper - of heart failure and cardiac death . The causes of trophy was induced using Angiotensin II (Ang cardiac hypertrophy are quite complex ; previous II). MIAT and miR-150 expression were quanti - studies 4,5 suggested that diverse factors , including fied using qRT-PCR. Rat heart-derived H9c2 physiological, mechanical, hormonal, and genetic cells were used as the in vitro model. Cardiac hypertrophic features were assessed by quanti - influence are all involved in the regulation . fying cardiac hypertrophic genes and measure - Long non-coding RNAs (lncRNAs) refers the ment of cell surface, protein synthesis and total non-protein-coding RNA transcripts longer than protein content. 200 nucleotides 6,7 . Recent studies suggest that RESULTS: MIAT is significantly increased in several dysregulated lncRNAs are associated Ang II induced cardiac hypertrophy in a mouse with the pathological development of cardiac hy - model and in H9c2 cells. MIAT siRNA substantial - ly alleviated the Ang II induced upregulation of pertrophy through transcriptional and post-tran - ANP, BNP and β-MHC in H9c2 cells and markedly scriptional regulation. At transcriptional level, attenuated the Ang II induced increase of the cell for example, lncRNA H19 is upregulated in surface area and the protein synthesis. MIAT pathological cardiac hypertrophy 8. Both H19 and overexpression in H9c2 cells significantly re - its encoded miR-675 can inhibit the hypertrophic duced the miR-150 expression. MIAT inhibition al - growth of cardiomyocytes, the effect of which is so partly restored the miR-150 levels under Ang II partly mediated by suppressing the expression of treatment. MiR-150 overexpression could attenu - 8 ate the Ang II induced upregulation of hyper - miR-675 target gene CaMKIIdelta . At the post- trophic marker genes and suppress the Ang II in - transcriptional level, lncRNA can function as duced hypertrophic phenotypes of the cells. miRNA sponge and modulate the development CONCLUSIONS: MIAT is significantly in - of cardiac hypertrophy. For example, lncRNA creased in Ang II induced cardiac hypertrophy and contributes to the pathological develop - CHRF can act as an endogenous sponge of miR- ment. MIAT can suppress miR-150 expression in 489 and increase the expression of miR-489 tar - cardiomyocytes and miR-150 is a downstream get gene myeloid differentiation primary re - effector of MIAT in the development of cardiac sponse gene 88 (Myd88), thereby promoting car - hypertrophy. diac hypertrophy 9. lncRNA-ROR can also pro - Key Words: mote cardiac hypertrophy via interacting with MIAT, miR-150, Cardiac hypertrophy . miR-133 10 . Myocardial infarction–associated transcript (MIAT), is an lncRNA predominantly expressed in heart and fetal brain tissue. Constant Introduction researches showed that dysregulated MIAT is in - volved in myocardial infarction 11,12 . However, Cardiac hypertrophy is an adaptive response of whether this lncRNA has a regulative effect on the heart to the increased cardiac load, which is cardiac hypertrophy is not clear.
Corresponding Author: Peng Wang, MD; e-mail: [email protected] 3653 X.-H. Zhu, Y.-X. Yuan, S.-L. Rao, P. Wang
Functionally, MIAT upregulation can lead to with 100 nM MIAT siRNA, 100 nM miR-150 microvascular dysfunction via enhancing en - mimics or pcDNA3.1-MIAT using Lipofecta - dothelial cell proliferation and migration 13 . In mine 2000 (Invitrogen) according to manufactur - both microvascular endothelial cells and lens ep - er’s instruction. ithelial cells, MIAT can act as a sponge of miR- 150 13,14 . miR-150 is an important miRNA with QRT-PCR Analysis inhibitive effect on pressure overload-induced Total RNA from the tissue and cell samples cardiac hypertrophy 15 and high glucose-induced were extracted using Trizol reagent (Invitrogen) cardiomyocyte hypertrophy 16 . Therefore, we hy - according to manufacturer’s instruction. The first pothesized that MIAT might exert a regulative strand cDNA were synthesized by reverse tran - effect on cardiac hypertrophy via acting as a scription using a First Strand Synthesis kit (Invit - miR-150 sponge. rogen, Carlsbad, CA, USA). QRT-PCR was per - formed to detect the expression of MIAT, ANP, BNP, β-MHC using gene specific primers and Materials and Methods SYBR ® Green qPCR MasterMix (Applied Biosystems, Foster City, CA, USA) in ABI 7500 Animals and Protocols Real-Time PCR Systems. The primers were: Animal based study was approved by the Re - search Commit tee of Zoucheng People’s Hospi - MIAT , 5’-TTTACTTTAACAGACCAGAA-3’ tal. All animal based studies followed the Guide (forward), for the Care and Use of Laboratory Animals (US 5’-CTCCTTTGTTGAATCCAT-30 and National Institutes of Health). Eight-week- (reverse); old male, healthy and specific pathogen-free ANP , 5’-ATCTGATGGATTTCAAGAACC-3’ C57BL/6J mice weighing 19-21 g was purchased (forward), from the Experimental Animal Center of the 5’-CTCTGAGACGGGTTGACTTC-3’ Shandong University. The mice were random - (reverse); ized into three groups (n=10/group): a blank BNP , 5’-ACAATCCACGATGCAGAAGCT- 3’ group without any treatment; a sham group only (forward), received PBS infusion; an Angiotensin II (Ang 5’-GGGCCTTGGTCCTTTGAGA-3’ II) (Sigma-Aldrich, St . Louis, MO, USA)-in - (reverse); fused group. The animals in Ang II group re - β-MHC , 5’-CCTCGCAATATCAAGGGAAA-3 ’ ceived Ang II dissolved in PBS with 10 µmol/L (forward), acetic acid at a dose of 2.5 µg/kg/min using a 5’-TACAGGTGCATCAGCTCCAG-3 subcutaneously implanted minipump (model (reverse). 2002, Alza, Moun tain View, CA, USA) for 15 days. The mice were housed in SPF conditions MiR-150 expression was determined by qRT- with a 12-h light/12-h dark cycle and with free PCR using the mirVana qRT-PCR miRNA De - access to drinking water and food. tection Kit and Primer Sets from Ambion as well as Taqman ® miRNA assays (Applied Biosys - Cell Culture and Treatment tems). The relative expression of the RNAs was Rat heart-derived H9c2 cells were cultured us - calculated using the 2 -∆∆ CT method. ing Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine Immunofluorescent Staining and serum (FBS) at 37 °C in a 5% CO 2 incubator. For Measurement of Cell Surface Area Ang II treatment, the cells were incubated with 1 Cells on coverslips were fixed with PBS con - µmol/L Ang II or PBS for 48 hours. MIAT siR - taining 4% paraformaldehyde, permeabilized in NA, miR-150 mimics and the scramble negative PBS containing 0.2% Triton X-100, and then controls were purchased from Ribobio blocked with PBS containing 3% BSA. After that (Guangzhou, China). The Full length of MIAT the cells were incubated with primary anti- α- cDNA was amplified and inserted into the sites actinin at a dilution of 1:100 in 1% goat serum between BamHI and XhoI of pcDNA3.1 plasmid overnight at 4°C, and then incubated with Alexa (Invitrogen, Carlsbad, CA, USA) and the recon - Fluor ® 594 goat anti-mouse IgG for 1 h at structed MIAT expression plasmids is named as 37°C. The coverslips were mounted onto glass pcDNA3.1-MIAT. H9c2 cells were transfected slides with SlowFade Gold antifade reagent with
3654 LncRNA MIAT enhances cardiac hypertrophy partly through sponging miR-150
DAPI. The cell surface area using a quantitative Results digital image analysis system (Image Pro-Plus version 7.0; Media Cybernetics, Rockville, MD, MIAT is Significantly Increased in Ang II USA) with a digital camera (Olympus IX-81, Induced Cardiac Hypertrophy Olympus, Tokyo, Japan) . 100 cells were random - Previous studies suggest that MIAT is an ly selected in three wells of different treatment. lncRNA that is significantly increased in patients with myocardial infarction and with dilated car - Measurement of [3H]leucine diomyopathy 12,18 . In this study, we firstly ex - Incorporation and Protein Content Assay plored the expression of MIAT in Ang II induced [3H]leucine incorporation was measured ac - cardiac hypertrophy in a mouse model. The re - cording to the method introduced in one previous sults showed that the hypertrophic cardiac tissues study 17 . Briefly, Cells were cultured in 24-well of the mice received 15 d administration of Ang plates in serum-free medium for 24 h. After indi - II had significantly increased MIAT expression cated treatment, the cells were pulsed with 1 (Figure 1A). In H9c2 cells, we also confirmed µCi/mL of [3H]leucine (Amersham Biosciences, that Ang II treatment induced a significant in - Piscataway, NJ, USA) for 4 hours before harvest. crease of MIAT expression (Figure 1B). There - After three times washing with PBS, the cells fore, we decided to further explore the biological were treated with 5% trichloroacetic acid for 30 function of MIAT using H9c2 cells as the in-vit - min. Finally, cells were solubilized in 500 µL of ro model. 1 mol/L NaOH and neutralized using 0.5 mol/L HCl. Then, an aliquot was taken to determine the Inhibition of MIAT Attenuates Ang II level of incorporated radioactivity using the Induced Cardiac Hypertrophy Beckman LS 3801 liquid scintillation counter Cardiac hypertrophy is associated with signifi - (Beckman, Fullerton, CA, USA). The total pro - cantly increased expression of the hypertrophic tein content per well was measured with a Modi - marker genes and the subsequent enhanced pro - fied Lowry Protein Assay Kit (Pierce, Rockford, tein synthesis and increased cell size 19 . There - IL, USA). fore, we firstly detected how MIAT suppression during Ang II treatment affected the hypertrophic Statistical Analysis marker genes, including ANP, BNP and β-MHC. Data analysis was performed using SPSS18.0 The results showed that MIAT siRNA substan - statistical software (SPSS Inc., Chicago, IL, tially alleviated Ang II induced upregulation of USA). Group comparison was conducted un - ANP, BNP and β-MHC in H9c2 cells (Figure paired t-tests. A two-tailed p<0.05 was consid - 2A). Another common feature of cardiac hyper - ered statistically significant. trophy is the increased cell surface area and the
Figure 1. MIAT is significantly increased in Ang II induced cardiac hypertrophy. A-B, QRT-PCR analysis of MIAT expres - sion in the mouse cardiac tissues of the three groups after indicated treatment (A) and in H9c2 cells after 48 hours treatment of Ang II (B) . N.S., not significant; ** p < 0.01.
3655 X.-H. Zhu, Y.-X. Yuan, S.-L. Rao, P. Wang
Figure 2. Inhibition of MIAT attenuates Ang II induced cardiac hypertrophy. A, QRT-PCR analysis of mRNA expression of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), -myosin heavy polypeptide (MHC) in H9c2 cells after Ang II treatment with or without MIAT knockdown. B-D, Immunofluoβrescent staining of -actinin and measurement of cell sur - face area (B) , the rate of protein synthesis (C) and the total protein content (D) in the Hα9c2 cardiomyocytes after Ang II treat - ment with or without MIAT knockdown. * p < 0.05, ** p < 0.01. enhanced protein synthesis. In this study, the cell mechanism. Previous studies showed that MI - surface area of the H9c2 cells was determined by AT could act as a miR-150 sponge in lens ep - α-actinin staining (Figure 2B). 48 h treatment ithelial cells and modulate cell proliferation, with Ang II stimulated a significant increase in apoptosis and migration 14 . In fact, miR-150 is the cell surface area. However, MIAT siRNA an important miRNA with inhibitive effect on markedly attenuated the increase (Figure 2B). In pressure overload-induced cardiac hypertro - addition, we also observed that MIAT siRNA phy 15 and high glucose-induced cardiomyocyte partly abrogated the Ang II induced higher level hypertrophy 16 . Bioinformatics analysis showed of [3H]leucine incorporation (Figure 2C) and to - that MIAT has three possible binding sites with tal protein content (Figure 2D). These results miR-150 (Figure 3A). Therefore, we hypothe - suggest that inhibition of MIAT attenuated Ang sized that the pathological effect of MIAT in II induced cardiac hypertrophy. cardiac hypertrophy might be related to its sponging of miR-150. To test this hypothesis, MIAT Suppresses miR-150 Expression in we firstly overexpressed MIAT in H9c2 cells H9c2 Cells (Figure 3B). MIAT overexpression significantly Since we confirmed the contribution of MI - reduced miR-150 expression in the cells (Figure AT in the development of hypertrophic charac - 3C). Ang II treatment also induced miR-150 teristics, we further investigated the underlying suppression in H9c2 cells (Figure 3D). Notably,
3656 LncRNA MIAT enhances cardiac hypertrophy partly through sponging miR-150
Figure 3. MIAT suppresses miR-150 expression in H9c2 cells. A, Bioinformatics analysis of the possible binding sites be - tween MIAT and miR-150. B-C, QRT-PCR analysis of MIAT (B) and miR-150 (C) expression in H9c2 cells after MIAT over - expression. D-E, QRT-PCR analysis of miR-150 expression in H9c2 cells after Ang II treatment (D) or with MIAT knock - down (E) . ** p < 0.01. inhibition of MIAT during Ang II treatment of cell surface area (Figure 4B) and also weak - partly restored miR-150 levels (Figure 3E). ened Ang II induced higher level of [3H]leucine These results suggest that MIAT can suppress incorporation (Figure 4C) and total protein syn - miR-150 expression in H9c2 cells. thesis (Figure 4D). These results suggest that miR-150 is a downstream effector of MIAT in MIAT Enhances Cardiac Hypertrophy the development of cardiac hypertrophy. Partially through Reducing miR-150 Since we verified the regulative effect of MI - AT1 on miR-150, we further studied the role of Discussion miR-150 in Ang II induced cardiac hypertrophy. MiR-150 overexpression attenuated Ang II in - In the past years, emerging evidence showed duced upregulation of hypertrophic marker genes that lncRNAs might have as either protective or (Figure 4A), suppressed Ang II induced increase enhancing effect in the development of cardiac
3657 X.-H. Zhu, Y.-X. Yuan, S.-L. Rao, P. Wang
Figure 4. MIAT enhances cardiac hypertrophy partially through reducing miR-150. A, QRT-PCR analysis of mRNA expres - sion of ANP, BNP, -MHC in H9c2 cells after Ang II treatment with or without miR-150 overexpression. B-D, Measurement of cell surface area β(B) , the rate of protein synthesis (C) and the total protein content (D) in the H9c2 cardiomyocytes after Ang II treatment with or without miR-150 overexpression. * p < 0.05, ** p < 0.01. hypertrophy. For example, Han et al 20 demon - Idelta 8. Besides the protective effect, other stud - strated that stress-induced myosin heavy-chain- ies also indicated that some lncRNAs can con - associated RNA transcripts (Mhrt) repression is tribute to the development of cardiac hypertro - essential for cardiomyopathy to develop, while phy mainly through the competitive endogenous restoring Mhrt to the pre-stress level showed RNA (ceRNA) mechanism, of which lncRNA protective effects on the heart from hypertrophy could interact with miRNA and indirectly inter - and failure 20 . Both H19 and its encoded miR- act with mRNAs through competing interac - 675 are upregulated in pathological cardiac hy - tions 21 . For example, lncRNA CHRF can act as pertrophy. Their upregulation can inhibit the an endogenous sponge of miR-489, which re - hypertrophic growth of cardiomyocytes, the ef - duces miR-489 expression 9. Via downregulating fect of which is partly mediated by suppressing miR-489, CHRF can upregulate Myd88 expres - the expression of miR-675 target gene CaMKI - sion and promote hypertrophy 9. Another study
3658 LncRNA MIAT enhances cardiac hypertrophy partly through sponging miR-150 observed that the expression of lncRNA-ROR Conclusions in hypertrophic heart and cardiomyocytes is ele - vated dramatically and can suppress miR-133 MIAT is significantly increased in Ang II in - expfession 10 . Overexpression of miR-133 re - duced cardiac hypertrophy and contributes to the duced the elevation of ROR and atennatured pathological development. MIAT can suppress ROR induced hypertrophy 10 . miR-150 expression in cardiomyocytes and miR- The pathological effect of MIAT in myocar - 150 is a downstream effector of MIAT in the de - dial infarction have been reported 11,12 . Vausort velopment of cardiac hypertrophy. et al 12 reported that MIAT is significantly high - er in whole blood from patients with non-ST- segment-elevation MI (NSTEMI) than in that –––––––––––––––– –-– –– Conflict of Interest from patients with ST-segment-elevation MI (STEMI), suggesting that MIAT is associated The Authors declare that there are no conflicts of interest. with chronic cardiomyopathy. Therefore, in this study, we firstly investigated the associa - tion between MIAT and cardiac hypertrophy References and we demonstrated that MIAT is significant - DIWAN A, D ORN GW, 2 ND . ly increased in Ang II induced cardiac hyper - 1) Decompensation of car - diac hypertrophy: cellular mechanisms and novel trophy. Knockdown of MIAT can reduce Ang therapeutic targets. Physiology (Bethesda) 2007; II induced upregulation of hypertrophic mark - 22: 56-64. ers and alleviated Ang II induced hypertrophic 2) DAIMEE UA, J ASTI S, H OBBS SK, C HEN L. Fat in the phenotypes in H9c2 cells. Therefore, we decid - right heart: the role of cardiac magnetic reso - ed to further investigate the underlying mecha - nance imaging in differentiating diffuse lipoma - nism. Previous researches found that in both tous hypertrophy of the right ventricle from ar - rhythmogenic right ventricular cardiomyopathy. microvascular endothelial cells and lens epithe - Eur Rev Med Pharmacol Sci 2016; 20: 1437- lial cells, MIAT functions as a sponge of miR- 1438. 13,14 150 . In fact, miR-150 has a well-recognized 3) ZHANG MJ, G U Y, W ANG H, Z HU PF, L IU XY, W U J. inhibitive effect on cardiac hypertrophy. Trans - Valsartan attenuates cardiac and renal hypertro - genic mice with miR-150 overexpression in the phy in rats with experimental cardiorenal syn - heart were resistant to cardiac hypertrophy and drome possibly through down-regulating galectin- fibrosis through down-regulation of serum re - 3 signaling. Eur Rev Med Pharmacol Sci 2016; 20: 345-354. sponse factor (SRF) 15 . In addition, miR-150 4) YAN W, G UO LR, Z HANG Q, S UN WZ, O' ROURKE ST, mimics can also prevent glucose-induced car - LIU KX, S UN CW . Chronic blockade of class I PI3- diomyocyte hypertrophy via downregulating kinase attenuates Ang II-induced cardiac hyper - p300 22 . Moreover, in transverse aortic constric - trophy and autophagic alteration. Eur Rev Med tion (TAC) mouse model, it was observed that Pharmacol Sci 2015; 19: 772-783. miR-150 could also inhibit cardiac fibroblast 5) CAO Y, L U L, L IU M, L I XC, S UN RR, Z HENG Y, Z HANG activation via reducing c-Myb expression 16 . PY . Impact of epigenetics in the management of cardiovascular disease: a review. Eur Rev Med Therefore, we investigated whether the patho - Pharmacol Sci 2014; 18: 3097-3104. logical effect of MIAT in cardiac hypertrophy 6) ZHANG N, Y ANG GQ, S HAO XM, W EI L. GAS5 modu - development is via sponging miR-150. In H9c2 lated autophagy is a mechanism modulating cis - cells, we confirmed that MIAT overexpression platin sensitivity in NSCLC cells. Eur Rev Med significantly reduced miR-150 expression, Pharmacol Sci 2016; 20: 2271-2277. while MIAT inhibition partly restored miR-150 7) LI DS, A INIWAER JL, S HEYHIDING I, Z HANG Z, Z HANG levels under Ang II treatment. Following func - LW . Identification of key long non-coding RNAs tional works further verified that miR-150 as competing endogenous RNAs for miRNA-mR - NA in lung adenocarcinoma. Eur Rev Med Phar - overexpression could attenuate Ang II induced macol Sci 2016; 20: 2285-2295. upregulation of hypertrophic marker genes and 8) LIU L, A N X, L I Z, S ONG Y, L I L, Z UO S, L IU N, Y ANG G, suppress Ang II induced hypertrophic pheno - WANG H, C HENG X, Z HANG Y, Y ANG X, W ANG J. The types of the cells. These results confirmed our H19 long noncoding RNA is a novel negative reg - hypothesis that MIAT could suppress miR-150 ulator of cardiomyocyte hypertrophy. Cardiovasc expression in cardiomyocytes and miR-150 is a Res 2016; 111: 56-65. downstream effector of MIAT in the develop - 9) WANG K, L IU F, Z HOU LY, L ONG B, Y UAN SM, W ANG ment of cardiac hypertrophy. Y, L IU CY, S UN T, Z HANG XJ, L I PF . The long non -
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