nach oben

Acta Diabetologica

Erschienen in:

27.04.2021 | Original Article

Long non-coding RNA KCNQ1OT1 increases the expression of PDCD4 by targeting miR-181a-5p, contributing to cardiomyocyte apoptosis in diabetic cardiomyopathy

verfasst von: Shuo-Fang Zhao, Ying-Xian Ye, Jin-Dong Xu, Yi He, Deng-Wen Zhang, Zheng-Yuan Xia, Sheng Wang

Erschienen in: Acta Diabetologica | Ausgabe 9/2021

Einloggen, um Zugang zu erhalten

Abstract

Aims

Diabetic cardiomyopathy (DCM) is a specific myocardial alteration in patients with diabetics. LncRNA KCNQ1OT1 has been previously demonstrated to be involved in various diabetic complications. Our aims are to further investigate the underlying regulatory mechanisms/pathways of KCNQ1OT1 in DCM.

Methods

In vitro and in vivo models of DCM were established in high glucose (HG)-treated human cardiomyocytes and in streptozotocin (STZ)-induced diabetic mice, respectively. Gene and protein expressions were examined by qPCR, western blotting and ELISA. Cell proliferation and apoptosis were determined by CCK8 assay, flow cytometry and TUNEL staining. The association between KCNQ1OT1 and miR-181a-5p, miR-181a-5p and PDCD4 was predicted using bioinformatics methods and subsequently confirmed by dual luciferase reporter and RNA immunoprecipitation assays. Mouse cardiac tissues were collected and analysed using HE staining, Masson’s staining and immunohistochemical analysis.

Results

KCNQ1OT1 and PDCD4 were upregulated in HG-treated human cardiomyocytes, while miR-181a-5p was downregulated. In addition, KCNQ1OT1 could negatively regulate miR-181a-5p expression; meanwhile, miR-181a-5p also negatively regulated PDCD4 expression. KCNQ1OT1 silencing suppressed the expression of inflammatory cytokines and cell apoptosis in vitro, whereas inhibition of miR-181a-5p abrogated those effects of KCNQ1OT1 knockdown. Moreover, overexpressed PDCD4 abolished the inhibition on inflammation and apoptosis caused by miR-181a-5p overexpression. Finally, KCNQ1OT1 knockdown reduced the expression of PDCD4 via regulating miR-181a-5p and inhibited myocardial inflammation and cardiomyocyte apoptosis in the in vivo DCM model.

Conclusions

Our findings suggest that KCNQ1OT1 and its target gene miR-181a-5p regulate myocardial inflammation and cardiomyocyte apoptosis by modulating PDCD4 in DCM.

Alonso N, Moliner P, Mauricio D (2018) Pathogenesis, clinical features and treatment of diabetic cardiomyopathy. Adv Exp Med Biol 1067:197–217. https://doi.org/10.1007/5584_2017_105CrossRefPubMed

Bhan A, Soleimani M, Mandal SS (2017) Long noncoding RNA and cancer: a new paradigm. Cancer Res 77:3965–3981. https://doi.org/10.1158/0008-5472.Can-16-2634CrossRefPubMed

Bugger H, Abel ED (2014) Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 57:660–671. https://doi.org/10.1007/s00125-014-3171-6CrossRefPubMedPubMedCentral

Chandramouli C, Reichelt ME, Curl CL et al (2018) Diastolic dysfunction is more apparent in STZ-induced diabetic female mice, despite less pronounced hyperglycemia. Sci Rep 8:2346. https://doi.org/10.1038/s41598-018-20703-8CrossRefPubMedPubMedCentral

Chang CP, Han P (2016) Epigenetic and lncRNA regulation of cardiac pathophysiology. Biochem Biophys Acta 1863:1767–1771. https://doi.org/10.1016/j.bbamcr.2016.03.005CrossRefPubMed

Chen Y, Tan S, Liu M, Li J (2018) LncRNA TINCR is downregulated in diabetic cardiomyopathy and relates to cardiomyocyte apoptosis. Scand Cardiovasc J SCJ 52:335–339. https://doi.org/10.1080/14017431.2018.1546896CrossRefPubMed

Chen Y, Zhang Z, Zhu D, Zhao W, Li F (2019) Long non-coding RNA MEG3 serves as a ceRNA for microRNA-145 to induce apoptosis of AC16 cardiomyocytes under high glucose condition. Biosci Rep. https://doi.org/10.1042/bsr20190444

Cheng Y, Li J, Wang C et al (2019) Inhibition of long non-coding RNA Malat1 attenuates high glucose-induced cardiomyocyte apoptosis via regulation of miR-181a-5p. Exp Anim. https://doi.org/10.1538/expanim.19-0058CrossRefPubMedPubMedCentral

Cheng Y, Li J, Wang C et al (2020) Inhibition of long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 attenuates high glucose-induced cardiomyocyte apoptosis via regulation of miR-181a-5p. Exp Anim 69:34–44. https://doi.org/10.1538/expanim.19-0058CrossRefPubMed

10.

Ding G, Zhou L, Shen T, Cao L (2018) IFN-gamma induces the upregulation of RFXAP via inhibition of miR-212-3p in pancreatic cancer cells: a novel mechanism for IFN-gamma response. Oncol Lett 15:3760–3765. https://doi.org/10.3892/ol.2018.7777CrossRefPubMedPubMedCentral

11.

Drilon A, Nagasubramanian R, Blake JF et al (2017) A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion-positive solid tumors. Cancer Discov 7:963–972. https://doi.org/10.1158/2159-8290.Cd-17-0507CrossRefPubMedPubMedCentral

12.

Feng SD, Yang JH, Yao CH et al (2017) Potential regulatory mechanisms of lncRNA in diabetes and its complications. Biochem Cell Biol Biochim Biol Cell 95:361–367. https://doi.org/10.1139/bcb-2016-0110CrossRef

13.

Iorio MV, Croce CM (2012) MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med 4:143–159. https://doi.org/10.1002/emmm.201100209CrossRefPubMedPubMedCentral

14.

Jia G, DeMarco VG, Sowers JR (2016) Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol 12:144–153. https://doi.org/10.1038/nrendo.2015.216CrossRefPubMed

15.

Jia G, Whaley-Connell A, Sowers JR (2018) Diabetic cardiomyopathy: a hyperglycaemia- and insulin-resistance-induced heart disease. Diabetologia 61:21–28. https://doi.org/10.1007/s00125-017-4390-4CrossRefPubMed

16.

Jiang Y, Du W, Chu Q et al (2018) Downregulation of long non-coding RNA Kcnq1ot1: an important mechanism of arsenic trioxide-induced long QT syndrome. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 45:192–202. https://doi.org/10.1159/000486357CrossRef

17.

Kanduri C (2011) Kcnq1ot1: a chromatin regulatory RNA. Semin Cell Dev Biol 22:343–350. https://doi.org/10.1016/j.semcdb.2011.02.020CrossRefPubMed

18.

Latronico MV, Elia L, Condorelli G, Catalucci D (2008) Heart failure: targeting transcriptional and post-transcriptional control mechanisms of hypertrophy for treatment. Int J Biochem Cell Biol 40:1643–1648. https://doi.org/10.1016/j.biocel.2008.03.002CrossRefPubMed

19.

Li JZ, Gao W, Ho WK et al (2016) The clinical association of programmed cell death protein 4 (PDCD4) with solid tumors and its prognostic significance: a meta-analysis. Chin J Cancer 35:95. https://doi.org/10.1186/s40880-016-0158-3CrossRefPubMedPubMedCentral

20.

Li Y, Lu J, Bao X et al (2016) MiR-499-5p protects cardiomyocytes against ischaemic injury via anti-apoptosis by targeting PDCD4. Oncotarget 7:35607–35617. https://doi.org/10.18632/oncotarget.9597CrossRefPubMedPubMedCentral

21.

Liu HJ, Fan YL, Liao HH et al (2017) Apigenin alleviates STZ-induced diabetic cardiomyopathy. Mol Cell Biochem 428:9–21. https://doi.org/10.1007/s11010-016-2913-9CrossRefPubMed

22.

Lo Furno D, Graziano AC, Caggia S et al (2013) Decrease of apoptosis markers during adipogenic differentiation of mesenchymal stem cells from human adipose tissue. Apoptosis Int J Program Cell Death 18:578–588. https://doi.org/10.1007/s10495-013-0830-xCrossRef

23.

Lozano-Bartolome J, Llaurado G, Portero-Otin M et al (2018) Altered expression of miR-181a-5p and miR-23a-3p is associated with obesity and TNFalpha-induced insulin resistance. J Clin Endocrinol Metab 103:1447–1458. https://doi.org/10.1210/jc.2017-01909CrossRefPubMed

24.

Lozano-Bartolomé J, Llauradó G, Portero-Otin M et al (2018) Altered expression of miR-181a-5p and miR-23a-3p is associated with obesity and TNFα-induced insulin resistance. J Clin Endocrinol Metab 103:1447–1458. https://doi.org/10.1210/jc.2017-01909CrossRefPubMed

25.

Meng Q, Li S, Liu Y et al (2019) Circular RNA circSCAF11 accelerates the glioma tumorigenesis through the miR-421/SP1/VEGFA axis. Mol Ther Nucleic Acids 17:669–677. https://doi.org/10.1016/j.omtn.2019.06.022CrossRefPubMedPubMedCentral

26.

Pant T, Dhanasekaran A, Fang J et al (2018) Current status and strategies of long noncoding RNA research for diabetic cardiomyopathy. BMC Cardiovasc Disord 18:197. https://doi.org/10.1186/s12872-018-0939-5CrossRefPubMedPubMedCentral

27.

Raut SK, Singh GB, Rastogi B et al (2016) miR-30c and miR-181a synergistically modulate p53–p21 pathway in diabetes induced cardiac hypertrophy. Mol Cell Biochem 417:191–203. https://doi.org/10.1007/s11010-016-2729-7CrossRefPubMed

28.

Romaine SP, Tomaszewski M, Condorelli G, Samani NJ (2015) MicroRNAs in cardiovascular disease: an introduction for clinicians. Heart (Br Card Soc) 101:921–928. https://doi.org/10.1136/heartjnl-2013-305402CrossRef

29.

Rotini A, Martinez-Sarra E, Pozzo E, Sampaolesi M (2018) Interactions between microRNAs and long non-coding RNAs in cardiac development and repair. Pharmacol Res 127:58–66. https://doi.org/10.1016/j.phrs.2017.05.029CrossRefPubMed

30.

Ruan Q, Wang T, Kameswaran V et al (2011) The microRNA-21-PDCD4 axis prevents type 1 diabetes by blocking pancreatic beta cell death. Proc Natl Acad Sci USA 108:12030–12035. https://doi.org/10.1073/pnas.1101450108CrossRefPubMedPubMedCentral

31.

Schmitz SU, Grote P, Herrmann BG (2016) Mechanisms of long noncoding RNA function in development and disease. Cell Mol Life Sci CMLS 73:2491–2509. https://doi.org/10.1007/s00018-016-2174-5CrossRefPubMed

32.

Shao J, Pan X, Yin X et al (2019) KCNQ1OT1 affects the progression of diabetic retinopathy by regulating miR-1470 and epidermal growth factor receptor. J Cell Physiol 234:17269–17279. https://doi.org/10.1002/jcp.28344CrossRefPubMed

33.

Shirjang S, Mansoori B, Asghari S et al (2019) MicroRNAs in cancer cell death pathways: apoptosis and necroptosis. Free Radic Biol Med 139:1–15. https://doi.org/10.1016/j.freeradbiomed.2019.05.017CrossRefPubMed

34.

Thomas CM, Yong QC, Seqqat R et al (2013) Direct renin inhibition prevents cardiac dysfunction in a diabetic mouse model: comparison with an angiotensin receptor antagonist and angiotensin-converting enzyme inhibitor. Clin Sci (Lond Engl) 124:529–541. https://doi.org/10.1042/cs20120448CrossRef

35.

van den Bosch MW, Palsson-Mcdermott E, Johnson DS, O’Neill LA (2014) LPS induces the degradation of programmed cell death protein 4 (PDCD4) to release Twist2, activating c-Maf transcription to promote interleukin-10 production. J Biol Chem 289:22980–22990. https://doi.org/10.1074/jbc.M114.573089CrossRefPubMedPubMedCentral

36.

Vausort M, Wagner DR, Devaux Y (2014) Long noncoding RNAs in patients with acute myocardial infarction. Circ Res 115:668–677. https://doi.org/10.1161/circresaha.115.303836CrossRefPubMed

37.

Wang Q, Dong Z, Liu X et al (2013) Programmed cell death-4 deficiency prevents diet-induced obesity, adipose tissue inflammation, and insulin resistance. Diabetes 62:4132–4143. https://doi.org/10.2337/db13-0097CrossRefPubMedPubMedCentral

38.

Wang Y, Yang X, Jiang A, Wang W, Li J, Wen J (2019) Methylation-dependent transcriptional repression of RUNX3 by KCNQ1OT1 regulates mouse cardiac microvascular endothelial cell viability and inflammatory response following myocardial infarction. FASEB J 33:13145–13160. https://doi.org/10.1096/fj.201900310RCrossRefPubMedPubMedCentral

39.

Xiao J, Pan Y, Li XH et al (2016) Cardiac progenitor cell-derived exosomes prevent cardiomyocytes apoptosis through exosomal miR-21 by targeting PDCD4. Cell Death Dis 7:e2277. https://doi.org/10.1038/cddis.2016.181CrossRefPubMedPubMedCentral

40.

Xue M, Zhuo Y, Shan B (2017) MicroRNAs, long noncoding RNAs, and their functions in human disease. Methods Mol Biol (Clifton, NJ) 1617:1–25. https://doi.org/10.1007/978-1-4939-7046-9_1CrossRef

41.

Yang F, Qin Y, Lv J et al (2018) Silencing long non-coding RNA Kcnq1ot1 alleviates pyroptosis and fibrosis in diabetic cardiomyopathy. Cell Death Dis 9:1000. https://doi.org/10.1038/s41419-018-1029-4CrossRefPubMedPubMedCentral

42.

Yang F, Qin Y, Wang Y et al (2018) LncRNA KCNQ1OT1 mediates pyroptosis in diabetic cardiomyopathy. Cell Physiol Biochem 50:1230–1244. https://doi.org/10.1159/000494576CrossRefPubMed

43.

Yang M, Zhai X, Ge T, Yang C, Lou G (2018) miR-181a-5p promotes proliferation and invasion and inhibits apoptosis of cervical cancer cells via regulating inositol polyphosphate-5-phosphatase A (INPP5A). Oncol Res 26:703–712. https://doi.org/10.3727/096504017x14982569377511CrossRefPubMedPubMedCentral

44.

Zhang J, Zhang M, Yang Z et al (2020) PDCD4 deficiency ameliorates left ventricular remodeling and insulin resistance in a rat model of type 2 diabetic cardiomyopathy. BMJ Open Diabetes Res Care. https://doi.org/10.1136/bmjdrc-2019-001081CrossRefPubMedPubMedCentral

45.

Zhang Y, Zhang L, Wang Y et al (2019) KCNQ1OT1, HIF1A-AS2 and APOA1-AS are promising novel biomarkers for diagnosis of coronary artery disease. Clin Exp Pharmacol Physiol 46:635–642. https://doi.org/10.1111/1440-1681.13094CrossRefPubMed

46.

Zheng D, Ma J, Yu Y et al (2015) Silencing of miR-195 reduces diabetic cardiomyopathy in C57BL/6 mice. Diabetologia 58:1949–1958. https://doi.org/10.1007/s00125-015-3622-8CrossRefPubMedPubMedCentral

47.

Zhou Q, Lv D, Chen P et al (2014) MicroRNAs in diabetic cardiomyopathy and clinical perspectives. Front Genet 5:185. https://doi.org/10.3389/fgene.2014.00185CrossRefPubMedPubMedCentral

48.

Zhu J, Yao K, Wang Q et al (2016) Ischemic postconditioning-regulated miR-499 protects the rat heart against ischemia/reperfusion injury by inhibiting apoptosis through PDCD4. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 39:2364–2380. https://doi.org/10.1159/000452506CrossRef

Titel: Long non-coding RNA KCNQ1OT1 increases the expression of PDCD4 by targeting miR-181a-5p, contributing to cardiomyocyte apoptosis in diabetic cardiomyopathy
verfasst von: Shuo-Fang Zhao
Ying-Xian Ye
Jin-Dong Xu
Yi He
Deng-Wen Zhang
Zheng-Yuan Xia
Sheng Wang
Publikationsdatum: 27.04.2021
Verlag: Springer Milan
Erschienen in: Acta Diabetologica / Ausgabe 9/2021
Print ISSN: 0940-5429
Elektronische ISSN: 1432-5233
DOI: https://doi.org/10.1007/s00592-021-01713-x

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Echinokokkose medikamentös behandeln oder operieren?

06.05.2024 DCK 2024 Kongressbericht

Die Therapie von Echinokokkosen sollte immer in spezialisierten Zentren erfolgen. Eine symptomlose Echinokokkose kann – egal ob von Hunde- oder Fuchsbandwurm ausgelöst – konservativ erfolgen. Wenn eine Op. nötig ist, kann es sinnvoll sein, vorher Zysten zu leeren und zu desinfizieren.

Umsetzung der POMGAT-Leitlinie läuft

03.05.2024 DCK 2024 Kongressbericht

Seit November 2023 gibt es evidenzbasierte Empfehlungen zum perioperativen Management bei gastrointestinalen Tumoren (POMGAT) auf S3-Niveau. Vieles wird schon entsprechend der Empfehlungen durchgeführt. Wo es im Alltag noch hapert, zeigt eine Umfrage in einem Klinikverbund.

Proximale Humerusfraktur: Auch 100-Jährige operieren?

01.05.2024 DCK 2024 Kongressbericht

Mit dem demographischen Wandel versorgt auch die Chirurgie immer mehr betagte Menschen. Von Entwicklungen wie Fast-Track können auch ältere Menschen profitieren und bei proximaler Humerusfraktur können selbst manche 100-Jährige noch sicher operiert werden.

Die „Zehn Gebote“ des Endokarditis-Managements

30.04.2024 Endokarditis Leitlinie kompakt

Worauf kommt es beim Management von Personen mit infektiöser Endokarditis an? Eine Kardiologin und ein Kardiologe fassen die zehn wichtigsten Punkte der neuen ESC-Leitlinie zusammen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Aims

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 9/2021

Circadian rhythm and gestational diabetes: working conditions, sleeping habits and lifestyle influence insulin dependency during pregnancy

Glucagon-like peptide-1 receptor agonists (GLP1-RA) in the treatment of mitochondrial diabetes

Correction to: Hyperglycemia at admission, comorbidities, and in-hospital mortality in elderly patients hospitalized in internal medicine wards: data from the RePoSI Registry

Mild periconceptional hyperglycemia: predictor of adverse fetomaternal outcomes in gestational diabetes?

Screening of postpartum diabetes in women with gestational diabetes: high-risk subgroups and areas for improvements—the STRONG observational study