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Exercise-induced circulating extracellular vesicles protect against cardiac ischemia–reperfusion injury

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Abstract

Extracellular vesicles (EVs) serve an important function as mediators of intercellular communication. Exercise is protective for the heart, although the signaling mechanisms that mediate this cardioprotection have not been fully elucidated. Here using nano-flow cytometry, we found a rapid increase in plasma EVs in human subjects undergoing exercise stress testing. We subsequently identified that serum EVs were increased by ~1.85-fold in mice after 3-week swimming. Intramyocardial injection of equivalent quantities of EVs from exercised mice and non-exercised controls provided similar protective effects against acute ischemia/reperfusion (I/R) injury in mice. However, injection of exercise-induced EVs in a quantity equivalent to the increase seen with exercise (1.85 swim group) significantly enhanced the protective effect. Similarly, treatment with exercise-induced increased EVs provided additional anti-apoptotic effect in H2O2-treated H9C2 cardiomyocytes mediated by the activation of ERK1/2 and HSP27 signaling. Finally, by treating H9C2 cells with insulin-like growth factor-1 to mimic exercise stimulus in vitro, we found an increased release of EVs from cardiomyocytes associated with ALIX and RAB35 activation. Collectively, our results show that exercise-induced increase in circulating EVs enhances the protective effects of endogenous EVs against cardiac I/R injury. Exercise-derived EVs might serve as a potent therapy for myocardial injury in the future.

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  • 08 October 2019

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Acknowledgements

This work was supported by the grants from National Natural Science Foundation of China (81570362 and 91639101 to J.J. Xiao and 81400647 to Y. Bei), the development fund for Shanghai talents (to J.J. Xiao), and the National Institutes of Health (NCATS Grant UH3 TR000901 to S. Das and U01 HL126497 to I.G.).

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Authors and Affiliations

  1. Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, 333 Nan Chen Road, Shanghai, 200444, China

    Yihua Bei, Tianzhao Xu, Dongchao Lv, Yongqin Li & Junjie Xiao

  2. Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China

    Pujiao Yu, Jiahong Xu & Lin Che

  3. Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA

    Avash Das, Ravi Shah & Saumya Das

  4. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA

    John Tigges, Vassilios Toxavidis & Ionita Ghiran

  5. Heart Failure Care Unit, Fuwai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China

    Yuhui Zhang

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  1. Yihua Bei
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Supplementary Figure 1 The mRNA levels of STAM1, TSG101, RAB11, and RAB27A were not changed in H9C2 cells treated with IGF-1 (n=6) (PDF 22 kb)

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Bei, Y., Xu, T., Lv, D. et al. Exercise-induced circulating extracellular vesicles protect against cardiac ischemia–reperfusion injury. Basic Res Cardiol 112, 38 (2017). https://doi.org/10.1007/s00395-017-0628-z

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