Functional role of circRNA CHRC through miR-431-5p/KLF15 signaling axis in the progression of heart failure

Yi Hu; Huaming Cao; Jie Sheng; Yizhuo Sun; Yuping Zhu; Qin Lin; Na Yi; Siyu He; Luying Peng; Li Li

doi:10.1016/j.jgg.2024.03.010

Volume 51 Issue 8

Aug. 2024

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Article Navigation > Journal of Genetics and Genomics > 2024 > 51(8): 844-854

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Functional role of circRNA CHRC through miR-431-5p/KLF15 signaling axis in the progression of heart failure

doi: 10.1016/j.jgg.2024.03.010

Yi Hu^a,b,c,
Huaming Cao^d,
Jie Sheng^a,b,c,
Yizhuo Sun^a,b,c,
Yuping Zhu^a,b,c,
Qin Lin^a,b,c,
Na Yi^a,b,c,
Siyu He^a,b,c,
Luying Peng^a,b,c,e,
Li Li^a,b,c,e

a. State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China;
b. Shanghai Arrhythmias Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China;
c. Laboratory of Molecular Genetics and Stem Cell Differentiation, Tongji University School of Medicine, Shanghai 200120, China;
d. Department of Cardiology, Shanghai Shibei Hospital, Shanghai 200435, China;
e. Research Units of Origin and Regulation of Heart Rhythm, Chinese Academy of Medical Sciences, Shanghai 200120, China

Funds:

This work was supported by the National Natural Science Foundation of China (32071109, 82070270, M-0048), the Shanghai Committee of Science and Technology (22ZR1463800, 21ZR1467000), the Shanghai Jing'an District Discipline Construction Project (2021PY03) and CAMS Innovation Fund for Medical Sciences (2019-I2M-5–053).

Received Date: 2023-12-13
Accepted Date: 2024-03-26
Rev Recd Date: 2024-03-25

Available Online: 2025-06-06

Publish Date: 2024-04-02

Abstract

Abstract

Pathological myocardial hypertrophy is a common early clinical manifestation of heart failure, with noncoding RNAs exerting regulatory influence. However, the molecular function of circular RNAs (circRNAs) in the progression from cardiac hypertrophy to heart failure remains unclear. To uncover functional circRNAs and identify the core circRNA signaling pathway in heart failure, we construct a global triple network (microRNA, circRNA, and mRNA) based on the competitive endogenous RNA (ceRNA) theory. We observe that cardiac hypertrophy-related circRNA (circRNA CHRC), within the ceRNA network, is down-regulated in both transverse aortic constriction mice and Ang-II—treated primary mouse cardiomyocytes. Silencing circRNA CHRC increases cross-sectional cell area, atrial natriuretic peptide, and β-myosin heavy chain levels in primary mouse cardiomyocytes. Further screening shows that circRNA CHRC targets the miR-431-5p/KLF15 axis implicated in heart failure progression in vivo and in vitro. Immunoprecipitation with anti-Ago2-RNA confirms the interaction between circRNA CHRC and miR-431-5p, while miR-431-5p mimics reverse Klf15 activation caused by circRNA CHRC overexpression. In summary, circRNA CHRC attenuates cardiac hypertrophy via sponging miR-431-5p to maintain the normal level of Klf15 expression.
- circRNA CHRC,
- Heart failure,
- ceRNA,
- miR-431-4p,
- Klf15

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References(42)

References

Agarwal, V., Bell, G.W., Nam, J.W., Bartel, D.P., 2015. Predicting effective microRNA target sites in mammalian mRNAs. Elife 4, e05005.

Ambros, V., 2004. The functions of animal microRNAs. Nature 431, 350-355.

Bartel, D.P., 2004. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281-297.

Betel, D., Koppal, A., Agius, P., Sander, C., Leslie, C., 2010. Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites. Genome Biol. 11, R90.

Bocchi, E.A., Vilas-Boas, F., Perrone, S., Caamano, A.G., Clausell, N., et al., 2005. I Latin American Guidelines for the Assessment and Management of Decompensated Heart Failure. Arq. Bras. Cardiol. 85 Suppl 3, 41-48.

Bragazzi, N.L., Zhong, W., Shu, J., Abu Much, A., Lotan, D., et al., 2021. Burden of heart failure and underlying causes in 195 countries and territories from 1990 to 2017. Eur. J. Prev. Cardiol. 28, 1682-1690.

Chen, L.L., 2020. The expanding regulatory mechanisms and cellular functions of circular RNAs. Nat. Rev. Mol. Cell Biol. 21, 475-490.

Conrad, N., Judge, A., Tran, J., Mohseni, H., Hedgecott, D., et al., 2018. Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals. Lancet 391, 572-580.

Deng, Y., Wang, J., Xie, G., Zeng, X., Li, H., 2019. Circ-HIPK3 Strengthens the Effects of Adrenaline in Heart Failure by MiR-17-3p - ADCY6 Axis. Int. J. Biol. Sci. 15, 2484-2496.

Du, W.W., Xu, J., Yang, W., Wu, N., Li, F., et al., 2021. A Neuroligin Isoform Translated by circNlgn Contributes to Cardiac Remodeling. Circ. Res. 129, 568-582.

Gene Ontology, C., 2006. The Gene Ontology (GO) project in 2006. Nucleic Acids Res. 34 (Database issue), D322-D326.

Geng, H., Chen, L., Su, Y., Xu, Q., Fan, M., et al., 2022. miR-431-5p regulates apoptosis of cardiomyocytes after acute myocardial infarction via targeting selenoprotein T. Physiol Res. 71, 55-62.

Glazar, P., Papavasileiou, P., Rajewsky, N., 2014. circBase: a database for circular RNAs. RNA 20, 1666-1670.

Griffiths-Jones, S., 2010. miRBase: microRNA sequences and annotation. Curr Protoc Bioinformatics Chapter 12, Unit 12, 11-10.

Halliday, B.P., Wassall, R., Lota, A.S., Khalique, Z., Gregson, J., et al., 2019. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet 393, 61-73.

Hansen, T.B., Wiklund, E.D., Bramsen, J.B., Villadsen, S.B., Statham, A.L., et al., 2011. miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. EMBO J. 30, 4414-4422.

Huang, D.W., Sherman, B.T., Tan, Q., Kir, J., Liu, D., et al., 2007. DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res 35(Web Server issue), W169-W175.

Huo, K.G., Richer, C., Berillo, O., Mahjoub, N., Fraulob-Aquino, J.C., et al., 2019. miR-431-5p Knockdown Protects Against Angiotensin II-Induced Hypertension and Vascular Injury. Hypertension 73, 1007-1017.

Kristensen, L.S., Okholm, T.L.H., Veno, M.T., Kjems, J., 2018. Circular RNAs are abundantly expressed and upregulated during human epidermal stem cell differentiation. Rna Biol. 15, 280-291.

Kruger, J., Rehmsmeier, M., 2006. RNAhybrid: microRNA target prediction easy, fast and flexible. Nucleic Acids Res. 34 (Web Server issue), W451-W454.

Li, H., Xu, J.D., Fang, X.H., Zhu, J.N., Yang, J., et al., 2020. Circular RNA circRNA_000203 aggravates cardiac hypertrophy via suppressing miR-26b-5p and miR-140-3p binding to Gata4. Cardiovasc. Res. 116, 1323-1334.

Li, X., Yang, L., Chen, L.L., 2018. The Biogenesis, Functions, and Challenges of Circular RNAs. Mol. Cell 71, 428-442.

Li, Y., Chen, B., Huang, S., 2018. Identification of circRNAs for miRNA Targets by Argonaute2 RNA Immunoprecipitation and Luciferase Screening Assays. Methods Mol. Biol. 1724, 209-218.

Love, M.I., Huber, W., Anders, S., 2014. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550.

Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J., et al., 2013. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495, 333-338.

Montgomery, R.L., Hullinger, T.G., Semus, H.M., Dickinson, B.A., Seto, A.G., et al., 2011. Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation 124, 1537-1547.

Patel, S.K., Ramchand, J., Crocitti, V., Burrell, L.M., 2018. Kruppel-Like Factor 15 Is Critical for the Development of Left Ventricular Hypertrophy. Int J Mol Sci 19.

Piwecka, M., Glazar, P., Hernandez-Miranda, L.R., Memczak, S., Wolf, S.A., et al., 2017. Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science 357.

Rybak-Wolf, A., Stottmeister, C., Glazar, P., Jens, M., Pino, N., et al., 2015. Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed. Mol Cell 58, 870-885.

Salmena, L., Poliseno, L., Tay, Y., Kats, L., Pandolfi, P.P., 2011. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146, 353-358.

Sanger, H.L., Klotz, G., Riesner, D., Gross, H.J., Kleinschmidt, A.K., 1976. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc. Natl. Acad. Sci. U. S. A. 73, 3852-3856.

Stanojevic, D., Hoey, T., Levine, M., 1989. Sequence-specific DNA-binding activities of the gap proteins encoded by hunchback and Kruppel in Drosophila. Nature 341, 331-335.

Sticht, C., De La Torre, C., Parveen, A., Gretz, N., 2018. miRWalk: An online resource for prediction of microRNA binding sites. PLoS ONE 13, e0206239.

Wahlquist, C., Jeong, D., Rojas-Munoz, A., Kho, C., Lee, A., et al., 2014. Inhibition of miR-25 improves cardiac contractility in the failing heart. Nature 508, 531-535.

Wang, J., Niu, Y., Luo, L., Lu, Z., Chen, Q., et al., 2022. Decoding ceRNA regulatory network in the pulmonary artery of hypoxia-induced pulmonary hypertension (HPH) rat model. Cell Biosci. 12, 27.

Wang, K., Long, B., Liu, F., Wang, J.X., Liu, C.Y., et al., 2016. A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223. Eur. Heart J. 37, 2602-2611.

Wang, W., Wang, L., Yang, M., Wu, C., Lan, R., et al., 2021. Circ-SIRT1 inhibits cardiac hypertrophy via activating SIRT1 to promote autophagy. Cell Death Dis. 12, 1069.

Werfel, S., Nothjunge, S., Schwarzmayr, T., Strom, T.M., Meitinger, T., et al., 2016. Characterization of circular RNAs in human, mouse and rat hearts. J. Mol. Cell Cardiol. 98, 103-107.

Wixon, J., Kell, D., 2000. The Kyoto encyclopedia of genes and genomes--KEGG. Yeast 17, 48-55.

Wu, S., Chen, L., Zhou, X., 2022. Circular RNAs in the regulation of cardiac hypertrophy. Mol. Ther. Nucleic Acids 27, 484-490.

Zhang, X., Yuan, S., Liu, J., Tang, Y., Wang, Y., et al., 2022. Overexpression of cytosolic long noncoding RNA cytb protects against pressure-overload-induced heart failure via sponging microRNA-103-3p. Mol. Ther. Nucleic Acids 27, 1127-1145.

Zheng, Q., Bao, C., Guo, W., Li, S., Chen, J., et al., 2016. Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat. Commun. 7, 11215.

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