, Volume 63, Issue 3, pp 480–488 | Cite as

Exosomal microRNA-29a mediates cardiac dysfunction and mitochondrial inactivity in obesity-related cardiomyopathy

  • Fengqin Li
  • Kuikui Zhang
  • Ting Xu
  • Wenjuan Du
  • Bo Yu
  • Youbin LiuEmail author
  • Honggang NieEmail author
Original Article



Present study aims to explore the pathophysiological role of microRNA (miR)-29a in the process of obesity-related cardiomyopathy in human subjects and mice.


The expression level of circulating exosomal miR-29a was measured in 37 lean and 30 obese human subjects, and correlated with cardiac parameters. The effects of miR-29a on mitochondrial activity and cardiac function were investigated by treatment of miR-29a sponge in primary mouse cardiomyocytes and diet-induced obesity-related cardiomyopathy in mice.


The increased circulating miR-29a level was closely associated with impaired human cardiac function, including ejection fraction (r = −0.2663, p < 0.05) and NT-proBNP levels (r = 0.4270, p < 0.001). Exosomes from obese human plasma mediated cardiomyocyte mitochondrial inactivity, but pre-treatment with miR-29a sponge attenuated the exosomal miR-29a-induced reduction of ATP production (p < 0.001), basal oxygen consumption (p < 0.01) and mitochondrial complex I activity (p < 0.01). In vivo mouse study, high fat diet damaged cardiac function, normal structure, and mitochondrial activity, whereas miR-29a sponge improved the cardiac status.


Present study uncovered the correlation between circulating miR-29a and cardiac parameters in human subjects, and provided solid evidence of the therapeutic application of miR-29a sponge in combating obesity-mediated cardiac dysfunction.


MicroRNA-29a Heart Obesity Exosome Mitochondria 



This study was supported by the match funding for the Key Laboratory of Myocardial Ischemia, Chinese Ministry Education (KL201316), The Heilongjiang Postdoctoral Fund (LBH-Z16133), and Chinese Postdoctoral Science Foundation (2017M611395).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Procedures involving the clinical trial and animal experiments were approved by Human Ethics Committee and Animal Policy and Welfare of Harbin Medical University Committee.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

12020_2018_1753_MOESM1_ESM.pdf (144 kb)
Figure S1 and S2
12020_2018_1753_MOESM2_ESM.docx (14 kb)
Supplementary Figure legend


  1. 1.
    H.B. Hubert, M. Feinleib, P.M. McNamara, W.P. Castelli, Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 67(5), 968–977 (1983)Google Scholar
  2. 2.
    L.F. Van Gaal, I.L. Mertens, C.E. De Block, Mechanisms linking obesity with cardiovascular disease. Nature 444(7121), 875–880 (2006). Google Scholar
  3. 3.
    T.B. Horwich, G.C. Fonarow, M.A. Hamilton, W.R. MacLellan, M.A. Woo, J.H. Tillisch, The relationship between obesity and mortality in patients with heart failure. J. Am. Coll. Cardiol. 38(3), 789–795 (2001)Google Scholar
  4. 4.
    G. O’Brien, Obesity and the risk of heart failure. N. Eng. J. Med. 347(23), 1887–1889 (2002).
  5. 5.
    A.B. Gustafsson, R.A. Gottlieb, Heart mitochondria: gates of life and death. Cardiovasc. Res. 77(2), 334–343 (2008). Google Scholar
  6. 6.
    M. Frisard, E. Ravussin, Energy metabolism and oxidative stress: impact on the metabolic syndrome and the aging process. Endocrine 29(1), 27–32 (2006). Google Scholar
  7. 7.
    J. Marin-Garcia, M.J. Goldenthal, G.W. Moe, Abnormal cardiac and skeletal muscle mitochondrial function in pacing-induced cardiac failure. Cardiovasc. Res. 52(1), 103–110 (2001)Google Scholar
  8. 8.
    J. Hirst, Mitochondrial complex I. Annu. Rev. Biochem. 82, 551–575 (2013). Google Scholar
  9. 9.
    J.G. Duncan, B.N. Finck, The PPARalpha-PGC-1alpha axis controls cardiac energy metabolism in healthy and diseased myocardium. Ppar. Res. 2008, 253817 (2008). Google Scholar
  10. 10.
    K. Drosatos, P.C. Schulze, Cardiac lipotoxicity: molecular pathways and therapeutic implications. Curr. Heart Fail. Rep. 10(2), 109–121 (2013). Google Scholar
  11. 11.
    I. Cundrle, P. Suk, V. Sramek, Z. Lacinova, M. Haluzik, Circadian leptin concentration changes in critically ill heart failure patients-preliminary results. Physiol. Res. 67(3), 505–508 (2018)Google Scholar
  12. 12.
    M.C. Borges, D.A. Lawlor, C. de Oliveira, J. White, B.L. Horta, A.J. Barros, Role of adiponectin in coronary heart disease risk: a mendelian randomization study. Circ. Res. 119(3), 491–499 (2016). Google Scholar
  13. 13.
    K.M. Choi, J.S. Lee, E.J. Kim, S.H. Baik, H.S. Seo, D.S. Choi, D.J. Oh, C.G. Park, Implication of lipocalin-2 and visfatin levels in patients with coronary heart disease. Eur. J. Endocrinol. 158(2), 203–207 (2008). Google Scholar
  14. 14.
    R. Shibata, N. Ouchi, M. Ito, S. Kihara, I. Shiojima, D.R. Pimentel, M. Kumada, K. Sato, S. Schiekofer, K. Ohashi, T. Funahashi, W.S. Colucci, K. Walsh, Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat. Med. 10(12), 1384–1389 (2004). Google Scholar
  15. 15.
    N.C. Lau, L.P. Lim, E.G. Weinstein, D.P. Bartel, An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294(5543), 858–862 (2001). Google Scholar
  16. 16.
    R.A. Boon, K. Iekushi, S. Lechner, T. Seeger, A. Fischer, S. Heydt, D. Kaluza, K. Treguer, G. Carmona, A. Bonauer, A.J. Horrevoets, N. Didier, Z. Girmatsion, P. Biliczki, J.R. Ehrlich, H.A. Katus, O.J. Muller, M. Potente, A.M. Zeiher, H. Hermeking, S. Dimmeler, MicroRNA-34a regulates cardiac ageing and function. Nature 495(7439), 107–110 (2013). Google Scholar
  17. 17.
    M. Kelly, R.D. Bagnall, R.E. Peverill, L. Donelan, L. Corben, M.B. Delatycki, C. Semsarian, A polymorphic miR-155 binding site in AGTR1 is associated with cardiac hypertrophy in Friedreich ataxia. J. Mol. Cell. Cardiol. 51(5), 848–854 (2011). Google Scholar
  18. 18.
    F. Wang, S.J. Zhang, X. Yao, D.M. Tian, K.Q. Zhang, D.M. She, F.F. Guo, Q.W. Zhai, H. Ying, Y. Xue, Circulating microRNA-1a is a biomarker of Graves’ disease patients with atrial fibrillation. Endocrine 57(1), 125–137 (2017). Google Scholar
  19. 19.
    R. Roncarati, C. Viviani Anselmi, M.A. Losi, L. Papa, E. Cavarretta, P. Da Costa Martins, C. Contaldi, G. Saccani Jotti, A. Franzone, L. Galastri, M.V. Latronico, M. Imbriaco, G. Esposito, L. De Windt, S. Betocchi, G. Condorelli, Circulating miR-29a, among other up-regulated microRNAs, is the only biomarker for both hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 63(9), 920–927 (2014). Google Scholar
  20. 20.
    Y. Ye, Z. Hu, Y. Lin, C. Zhang, J.R. Perez-Polo, Downregulation of microRNA-29 by antisense inhibitors and a PPAR-gamma agonist protects against myocardial ischaemia-reperfusion injury. Cardiovasc. Res. 87(3), 535–544 (2010). Google Scholar
  21. 21.
    A.A. Derda, S. Thum, J.M. Lorenzen, U. Bavendiek, J. Heineke, B. Keyser, M. Stuhrmann, R.C. Givens, P.J. Kennel, P.C. Schulze, J.D. Widder, J. Bauersachs, T. Thum, Blood-based microRNA signatures differentiate various forms of cardiac hypertrophy. Int. J. Cardiol. 196, 115–122 (2015). Google Scholar
  22. 22.
    L. Fang, A.H. Ellims, X.L. Moore, D.A. White, A.J. Taylor, J. Chin-Dusting, A.M. Dart, Circulating microRNAs as biomarkers for diffuse myocardial fibrosis in patients with hypertrophic cardiomyopathy. J. Transl. Med. 13, 314 (2015). Google Scholar
  23. 23.
    L. Wang, X. Niu, J. Hu, H. Xing, M. Sun, J. Wang, Q. Jian, H. Yang, After myocardial ischemia-reperfusion, miR-29a, and Let7 could affect apoptosis through regulating IGF-1. Biomed. Res. Int. 2015, 245412 (2015). Google Scholar
  24. 24.
    Y. Zhang, X.R. Huang, L.H. Wei, A.C. Chung, C.M. Yu, H.Y. Lan, miR-29b as a therapeutic agent for angiotensin II-induced cardiac fibrosis by targeting TGF-beta/Smad3 signaling. Mol. Ther. 22(5), 974–985 (2014). Google Scholar
  25. 25.
    X. Cao, J. Wang, Z. Wang, J. Du, X. Yuan, W. Huang, J. Meng, H. Gu, Y. Nie, B. Ji, S. Hu, Z. Zheng, MicroRNA profiling during rat ventricular maturation: a role for miR-29a in regulating cardiomyocyte cell cycle re-entry. FEBS Lett. 587(10), 1548–1555 (2013). Google Scholar
  26. 26.
    W.M. Yang, H.J. Jeong, S.Y. Park, W. Lee, Induction of miR-29a by saturated fatty acids impairs insulin signaling and glucose uptake through translational repression of IRS-1 in myocytes. FEBS Lett. 588(13), 2170–2176 (2014). Google Scholar
  27. 27.
    J. Dooley, J.E. Garcia-Perez, J. Sreenivasan, S.M. Schlenner, R. Vangoitsenhoven, A.S. Papadopoulou, L. Tian, S. Schonefeldt, L. Serneels, C. Deroose, K.A. Staats, B. Van der Schueren, B. De Strooper, O.P. Mc Guinness, C. Mathieu, A. Liston, The microRNA-29 family dictates the balance between homeostatic and pathological glucose handling in diabetes and obesity. Diabetes 65(1), 53–61 (2016). Google Scholar
  28. 28.
    Y. Pan, Y. Wang, Y. Zhao, K. Peng, W. Li, Y. Wang, J. Zhang, S. Zhou, Q. Liu, X. Li, L. Cai, G. Liang, Inhibition of JNK phosphorylation by a novel curcumin analog prevents high glucose-induced inflammation and apoptosis in cardiomyocytes and the development of diabetic cardiomyopathy. Diabetes 63(10), 3497–3511 (2014). Google Scholar
  29. 29.
    H. Nie, C. Song, D. Wang, S. Cui, T. Ren, Z. Cao, Q. Liu, Z. Chen, X. Chen, Y. Zhou, MicroRNA-194 inhibition improves dietary-induced non-alcoholic fatty liver disease in mice through targeting on FXR. Biochim. Biophys. Acta 1863(12), 3087–3094 (2017). Google Scholar
  30. 30.
    P.J. Hunt, A.M. Richards, M.G. Nicholls, T.G. Yandle, R.N. Doughty, E.A. Espiner, Immunoreactive amino-terminal pro-brain natriuretic peptide (NT-PROBNP): a new marker of cardiac impairment. Clin. Endocrinol. 47(3), 287–296 (1997)Google Scholar
  31. 31.
    H. Valadi, K. Ekstrom, A. Bossios, M. Sjostrand, J.J. Lee, J.O. Lotvall, Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9(6), 654–659 (2007). Google Scholar
  32. 32.
    M. Whitham, B.L. Parker, M. Friedrichsen, J.R. Hingst, M. Hjorth, W.E. Hughes, C.L. Egan, L. Cron, K.I. Watt, R.P. Kuchel, N. Jayasooriah, E. Estevez, T. Petzold, C.M. Suter, P. Gregorevic, B. Kiens, E.A. Richter, D.E. James, J.F.P. Wojtaszewski, M.A. Febbraio, Extracellular vesicles provide a means for tissue crosstalk during exercise. Cell. Metab. 27(1), 237–251 e234 (2018). Google Scholar
  33. 33.
    K.M. Davies, M. Strauss, B. Daum, J.H. Kief, H.D. Osiewacz, A. Rycovska, V. Zickermann, W. Kuhlbrandt, Macromolecular organization of ATP synthase and complex I in whole mitochondria. Proc. Natl. Acad. Sci. USA 108(34), 14121–14126 (2011). Google Scholar
  34. 34.
    F.C. Yin, H.A. Spurgeon, K. Rakusan, M.L. Weisfeldt, E.G. Lakatta, Use of tibial length to quantify cardiac hypertrophy: application in the aging rat. Am. J. Physiol. 243(6), H941–H947 (1982). Google Scholar
  35. 35.
    F.S. Loffredo, M.L. Steinhauser, S.M. Jay, J. Gannon, J.R. Pancoast, P. Yalamanchi, M. Sinha, C. Dall’Osso, D. Khong, J.L. Shadrach, C.M. Miller, B.S. Singer, A. Stewart, N. Psychogios, R.E. Gerszten, A.J. Hartigan, M.J. Kim, T. Serwold, A.J. Wagers, R.T. Lee, Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153(4), 828–839 (2013). Google Scholar
  36. 36.
    S. De Rosa, B. Arcidiacono, E. Chiefari, A. Brunetti, C. Indolfi, D.P. Foti, Type 2 diabetes mellitus and cardiovascular disease: genetic and epigenetic links. Front. Endocrinol. 9, 2 (2018). Google Scholar
  37. 37.
    C.L. Kurtz, B.C. Peck, E.E. Fannin, C. Beysen, J. Miao, S.R. Landstreet, S. Ding, V. Turaga, P.K. Lund, S. Turner, S.B. Biddinger, K.C. Vickers, P. Sethupathy, MicroRNA-29 fine-tunes the expression of key FOXA2-activated lipid metabolism genes and is dysregulated in animal models of insulin resistance and diabetes. Diabetes 63(9), 3141–3148 (2014). Google Scholar
  38. 38.
    Z. Yang, L. Wu, X. Zhu, J. Xu, R. Jin, G. Li, F. Wu, MiR-29a modulates the angiogenic properties of human endothelial cells. Biochem. Biophys. Res. Commun. 434(1), 143–149 (2013). Google Scholar
  39. 39.
    Q. Lin, Z. Yun, The hypoxia-inducible factor pathway in adipocytes: the role of HIF-2 in adipose inflammation and hypertrophic cardiomyopathy. Front. Endocrinol. 6, 39 (2015). Google Scholar
  40. 40.
    V.J. Dzau, Autocrine and paracrine mechanisms in the pathophysiology of heart failure. Am. J. Cardiol. 70(10), 4C–11C (1992)Google Scholar
  41. 41.
    J.F. Keaney Jr., M.G. Larson, R.S. Vasan, P.W. Wilson, I. Lipinska, D. Corey, J.M. Massaro, P. Sutherland, J.A. Vita, E.J. Benjamin, S. Framingham, Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study. Arterioscler. Thromb. Vasc. Biol. 23(3), 434–439 (2003). Google Scholar
  42. 42.
    K. Denzer, M.J. Kleijmeer, H.F. Heijnen, W. Stoorvogel, H.J. Geuze, Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J. Cell. Sci. 113(Pt 19), 3365–3374 (2000)Google Scholar
  43. 43.
    X. Wang, H. Gu, W. Huang, J. Peng, Y. Li, L. Yang, D. Qin, K. Essandoh, Y. Wang, T. Peng, G.C. Fan, Hsp20-mediated activation of exosome biogenesis in cardiomyocytes improves cardiac function and angiogenesis in diabetic mice. Diabetes 65(10), 3111–3128 (2016). Google Scholar
  44. 44.
    E.E. Creemers, A.J. Tijsen, Y.M. Pinto, Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease? Circ. Res. 110(3), 483–495 (2012). Google Scholar
  45. 45.
    M.J. Rahman, D. Regn, R. Bashratyan, Y.D. Dai, Exosomes released by islet-derived mesenchymal stem cells trigger autoimmune responses in NOD mice. Diabetes 63(3), 1008–1020 (2014). Google Scholar
  46. 46.
    G. Zhang, Q. Wang, R. Xu, Therapeutics based on microRNA: a new approach for liver cancer. Curr. Genom. 11(5), 311–325 (2010). Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of CardiologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
  2. 2.Department of CardiologyThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina

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