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A novel circ_0018553 protects against angiotensin-induced cardiac hypertrophy in cardiomyocytes by modulating the miR-4731/SIRT2 signaling pathway

Hypertension Research volume 46, pages 421–436 (2023)Cite this article

Abstract

Due to the complicated pathophysiology of cardiac hypertrophy, there are no effective therapies for the treatment of pathological cardiac hypertrophy. Accumulating evidence has demonstrated that circRNAs participate in the pathophysiology of cardiac hypertrophy. In this study, we investigated the regulatory mechanisms of the novel circ_0018553 in angiotensin II (Ang II)-induced cardiac hypertrophy. Circ_0018553 was enriched in endothelial progenitor cell (EPC)-derived exosomes, and circ_0018553 expression was downregulated in a cellular model of Ang II-induced cardiac hypertrophy. Silencing circ_0018553 promoted cardiac hypertrophy in the Ang II-induced cardiac hypertrophy cellular model, while overexpression of circ_0018553 significantly attenuated Ang II-induced cardiac hypertrophy in cardiomyocytes. Moreover, mechanistic studies revealed that circ_0018553 acted as a sponge for miR-4731 and that miR-4731 repressed sirtuin 2 (SIRT2) expression by targeting the 3′UTR of SIRT2. MiR-4731 overexpression promoted cardiac hypertrophy in the Ang II-induced cardiac hypertrophy cellular model, while inhibition of miR-4731 significantly attenuated Ang II-induced cardiac hypertrophy in cardiomyocytes. The rescue experiments showed that miR-4731 overexpression attenuated the protective effects of circ_0018553 overexpression on the cardiac hypertrophy induced by Ang II; SIRT2 silencing also attenuated the protective effects of miR-4731 inhibition on the Ang II-induced cardiac hypertrophy. In conclusion, our results indicated that EPC-derived exosomal circ_0018553 protected against Ang II-induced cardiac hypertrophy by modulating the miR-4731/SIRT2 signaling pathway.

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Data availability

The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request.

References

  1. Nakamura M, Sadoshima J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol. 2018;15:387–407.

    Article  CAS  Google Scholar 

  2. Shimizu I, Minamino T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol. 2016;97:245–62.

    Article  CAS  Google Scholar 

  3. Frey N, Olson EN. Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol. 2003;65:45–79.

    Article  CAS  Google Scholar 

  4. Oldfield CJ, Duhamel TA, Dhalla NS. Mechanisms for the transition from physiological to pathological cardiac hypertrophy. Can J Physiol Pharmacol. 2020;98:74–84.

    Article  CAS  Google Scholar 

  5. Zhu L, Li C, Liu Q, Xu W, Zhou X. Molecular biomarkers in cardiac hypertrophy. J Cell Mol Med. 2019;23:1671–7.

    Article  Google Scholar 

  6. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200:373–83.

    Article  CAS  Google Scholar 

  7. Gu S, Zhang W, Chen J, Ma R, Xiao X, Ma X, et al. EPC-derived microvesicles protect cardiomyocytes from Ang II-induced hypertrophy and apoptosis. PLoS One. 2014;9:e85396.

    Article  Google Scholar 

  8. Ranghino A, Cantaluppi V, Grange C, Vitillo L, Fop F, Biancone L, et al. Endothelial progenitor cell-derived microvesicles improve neovascularization in a murine model of hindlimb ischemia. Int J Immunopathol Pharmacol. 2012;25:75–85.

    Article  CAS  Google Scholar 

  9. Hayakawa K, Chan SJ, Mandeville ET, Park JH, Bruzzese M, Montaner J, et al. Protective effects of endothelial progenitor cell-derived extracellular mitochondria in brain endothelium. Stem Cells. 2018;36:1404–10.

    Article  CAS  Google Scholar 

  10. Yu X, Odenthal M, Fries JW. Exosomes as miRNA carriers: formation-function-future. Int J Mol Sci. 2016;17:2028.

  11. Zhou Y, Li P, Goodwin AJ, Cook JA, Halushka PV, Chang E, et al. Exosomes from endothelial progenitor cells improve the outcome of a murine model of sepsis. Mol Ther. 2018;26:1375–84.

    Article  CAS  Google Scholar 

  12. Altesha MA, Ni T, Khan A, Liu K, Zheng X. Circular RNA in cardiovascular disease. J Cell Physiol. 2019;234:5588–600.

    Article  CAS  Google Scholar 

  13. Chen LL, Yang L. Regulation of circRNA biogenesis. RNA Biol. 2015;12:381–8.

    Article  Google Scholar 

  14. Du WW, Zhang C, Yang W, Yong T, Awan FM, Yang BB. Identifying and characterizing circRNA-protein interaction. Theranostics. 2017;7:4183–91.

    Article  CAS  Google Scholar 

  15. Li R, Jiang J, Shi H, Qian H, Zhang X, Xu W. CircRNA: a rising star in gastric cancer. Cell Mol Life Sci. 2020;77:1661–80.

    Article  CAS  Google Scholar 

  16. Li H, Xu JD, Fang XH, Zhu JN, Yang J, Pan R, et al. Circular RNA circRNA_000203 aggravates cardiac hypertrophy via suppressing miR-26b-5p and miR-140-3p binding to Gata4. Cardiovascular Res. 2020;116:1323–34.

    Article  CAS  Google Scholar 

  17. Wang K, Long B, Liu F, Wang JX, Liu CY, Zhao B, et al. A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223. Eur Heart J. 2016;37:2602–11.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  19. Barwari T, Joshi A, Mayr M. MicroRNAs in cardiovascular disease. J Am Coll Cardiol. 2016;68:2577–84.

    Article  CAS  Google Scholar 

  20. Yuan J, Liu H, Gao W, Zhang L, Ye Y, Yuan L, et al. MicroRNA-378 suppresses myocardial fibrosis through a paracrine mechanism at the early stage of cardiac hypertrophy following mechanical stress. Theranostics. 2018;8:2565–82.

    Article  CAS  Google Scholar 

  21. Oh JG, Watanabe S, Lee A, Gorski PA, Lee P, Jeong D, et al. miR-146a suppresses SUMO1 expression and induces cardiac dysfunction in maladaptive hypertrophy. Circulation Res. 2018;123:673–85.

    Article  CAS  Google Scholar 

  22. Li Z, Song Y, Liu L, Hou N, An X, Zhan D, et al. miR-199a impairs autophagy and induces cardiac hypertrophy through mTOR activation. Cell Death Differ. 2017;24:1205–13.

    Article  CAS  Google Scholar 

  23. Ucar A, Gupta SK, Fiedler J, Erikci E, Kardasinski M, Batkai S, et al. The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nat Commun. 2012;3:1078.

    Article  Google Scholar 

  24. Albrecht-Schgoer K, Schgoer W, Holfeld J, Theurl M, Wiedemann D, Steger C, et al. The angiogenic factor secretoneurin induces coronary angiogenesis in a model of myocardial infarction by stimulation of vascular endothelial growth factor signaling in endothelial cells. Circulation. 2012;126:2491–501.

    Article  CAS  Google Scholar 

  25. Davidson MM, Nesti C, Palenzuela L, Walker WF, Hernandez E, Protas L, et al. Novel cell lines derived from adult human ventricular cardiomyocytes. J Mol Cell Cardiol. 2005;39:133–47.

    Article  CAS  Google Scholar 

  26. Huang Y, Chen L, Feng Z, Chen W, Yan S, Yang R, et al. EPC-derived exosomal miR-1246 and miR-1290 regulate phenotypic changes of fibroblasts to endothelial cells to exert protective effects on myocardial infarction by targeting ELF5 and SP1. Front Cell Dev Biol. 2021;9:647763.

  27. Ke X, Yang R, Wu F, Wang X, Liang J, Hu X, et al. Exosomal miR-218-5p/miR-363-3p from endothelial progenitor cells ameliorate myocardial infarction by targeting the p53/JMY signaling pathway. Oxid Med Cell Longev. 2021;2021:5529430.

    Article  Google Scholar 

  28. Ma X, Wang J, Li J, Ma C, Chen S, Lei W, et al. Loading MiR-210 in endothelial progenitor cells derived exosomes boosts their beneficial effects on hypoxia/reoxygeneation-injured human endothelial cells via protecting mitochondrial function. Cell Physiol Biochem. 2018;46:664–75.

    Article  CAS  Google Scholar 

  29. Ni H, Li W, Zhuge Y, Xu S, Wang Y, Chen Y, et al. Inhibition of circHIPK3 prevents angiotensin II-induced cardiac fibrosis by sponging miR-29b-3p. Int J Cardiol. 2019;292:188–96.

    Article  Google Scholar 

  30. Xu X, Wang J, Wang X. Silencing of circHIPK3 inhibits pressure overload-induced cardiac hypertrophy and dysfunction by sponging miR-185-3p. Drug Des Dev Ther. 2020;14:5699–710.

    Article  CAS  Google Scholar 

  31. Lim TB, Aliwarga E, Luu TDA, Li YP, Ng SL, Annadoray L, et al. Targeting the highly abundant circular RNA circSlc8a1 in cardiomyocytes attenuates pressure overload induced hypertrophy. Cardiovascular Res. 2019;115:1998–2007.

    Article  CAS  Google Scholar 

  32. Wang Y, Ma J, Li R, Gao X, Wang H, Jiang G. LncRNA TMPO-AS1 serves as a sponge for miR-4731-5p modulating breast cancer progression through FOXM1. Am J Transl Res. 2021;13:11094–106.

    CAS  Google Scholar 

  33. Yan Z, Zhang W, Xiong Y, Wang Y, Li Z. Long noncoding RNA FLVCR1-AS1 aggravates biological behaviors of glioma cells via targeting miR-4731-5p/E2F2 axis. Biochem Biophys Res Commun. 2020;521:716–20.

    Article  CAS  Google Scholar 

  34. Gomes P, Fleming Outeiro T, Cavadas C. Emerging role of Sirtuin 2 in the regulation of mammalian metabolism. Trends Pharmacol Sci. 2015;36:756–68.

    Article  CAS  Google Scholar 

  35. Tang X, Chen XF, Wang NY, Wang XM, Liang ST, Zheng W, et al. SIRT2 acts as a cardioprotective deacetylase in pathological cardiac hypertrophy. Circulation. 2017;136:2051–67.

    Article  CAS  Google Scholar 

  36. Mei ZL, Wang HB, Hu YH, Xiong L. CSN6 aggravates Ang II-induced cardiomyocyte hypertrophy via inhibiting SIRT2. Exp Cell Res. 2020;396:112245.

    Article  CAS  Google Scholar 

  37. Gu W, Cheng Y, Wang S, Sun T, Li Z. PHD finger protein 19 promotes cardiac hypertrophy via epigenetically regulating SIRT2. Cardiovascular Toxicol. 2021;21:451–61.

    Article  CAS  Google Scholar 

  38. Sarikhani M, Maity S, Mishra S, Jain A, Tamta AK, Ravi V, et al. SIRT2 deacetylase represses NFAT transcription factor to maintain cardiac homeostasis. J Biol Chem. 2018;293:5281–94.

    Article  CAS  Google Scholar 

  39. Hardie DG. AMPK–sensing energy while talking to other signaling pathways. Cell Metab. 2014;20:939–52.

    Article  CAS  Google Scholar 

  40. Lopaschuk GD, Karwi QG, Tian R, Wende AR, Abel ED. Cardiac energy metabolism in heart failure. Circulation Res. 2021;128:1487–513.

    Article  CAS  Google Scholar 

  41. Feng Y, Zhang Y, Xiao H. AMPK and cardiac remodelling. Sci China Life Sci. 2018;61:14–23.

    Article  CAS  Google Scholar 

  42. Viollet B, Athea Y, Mounier R, Guigas B, Zarrinpashneh E, Horman S, et al. AMPK: lessons from transgenic and knockout animals. Front Biosci (Landmark Ed). 2009;14:19–44.

    Article  CAS  Google Scholar 

  43. Aiyasiding X, Liao HH, Feng H, Zhang N, Lin Z, Ding W, et al. Liquiritin attenuates pathological cardiac hypertrophy by activating the PKA/LKB1/AMPK pathway. Front Pharmacol. 2022;13:870699.

    Article  CAS  Google Scholar 

  44. Hinrichsen R, Hansen AH, Haunsø S, Busk PK. Phosphorylation of pRb by cyclin D kinase is necessary for development of cardiac hypertrophy. Cell Prolif. 2008;41:813–29.

    Article  CAS  Google Scholar 

  45. Busk PK, Bartkova J, Strøm CC, Wulf-Andersen L, Hinrichsen R, Christoffersen TE, et al. Involvement of cyclin D activity in left ventricle hypertrophy in vivo and in vitro. Cardiovascular Res. 2002;56:64–75.

    Article  CAS  Google Scholar 

  46. Carvalho MR, Mendonça MLM, Oliveira JML, Romanenghi RB, Morais CS, Ota GE, et al. Influence of high-intensity interval training and intermittent fasting on myocardium apoptosis pathway and cardiac morphology of healthy rats. Life Sci. 2021;264:118697.

    Article  CAS  Google Scholar 

  47. Yang J, Chen YN, Xu ZX, Mou Y, Zheng LR. Alteration of RhoA prenylation ameliorates cardiac and vascular remodeling in spontaneously hypertensive rats. Cell Physiol Biochem. 2016;39:229–41.

    Article  CAS  Google Scholar 

  48. Tong YF, Wang Y, Ding YY, Li JM, Pan XC, Lu XL, et al. Cyclin-dependent kinase inhibitor p21WAF1/CIP1 facilitates the development of cardiac hypertrophy. Cell Physiol Biochem. 2017;42:1645–56.

    Article  CAS  Google Scholar 

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Funding

This work was supported by grants from the Shenzhen Science and Technology Program (JCYJ20180302173927276, JCYJ20180703145002040, JCYJ20180302150203732); Baoan district of the Shenzhen Science and Technology Plan Basic Research Project (2020JD479); and the Fund of the “Sanming” Project of Medicine in Shenzhen (SZSM201911017).

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  1. These authors contributed equally: Huihua Zuo, Liang Li

Authors and Affiliations

  1. Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, Shenzhen Sun Yat-sen Cardiovascular Hospital, Shenzhen, 518057, China

    Huihua Zuo, Xiaoqing Wang, Shiyu Chen, Zhiyong Liao, Huanjun Ruan, Teng Li & Junyu Chen

  2. Department of Cardiology, Shenzhen Bao’an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, 518057, China

    Liang Li & Shanyin Wei

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Contributions

HZ, TL, and JC: study design. HZ, LL, and XW: investigation. SC and ZL: data collection/entry, SW and HR: data analysis and statistics. HZ, TL, and JC: preparation of manuscript. All authors read and approved the final manuscript.

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Correspondence to Teng Li or Junyu Chen.

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Zuo, H., Li, L., Wang, X. et al. A novel circ_0018553 protects against angiotensin-induced cardiac hypertrophy in cardiomyocytes by modulating the miR-4731/SIRT2 signaling pathway. Hypertens Res 46, 421–436 (2023). https://doi.org/10.1038/s41440-022-01111-y

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