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

• Published in: Basic research in cardiology Vol. 112; no. 4; pp. 38 - 15
• Main Authors: Bei, Yihua, Xu, Tianzhao, Lv, Dongchao, Yu, Pujiao, Xu, Jiahong, Che, Lin, Das, Avash, Tigges, John, Toxavidis, Vassilios, Ghiran, Ionita, Shah, Ravi, Li, Yongqin, Zhang, Yuhui, Das, Saumya, Xiao, Junjie
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2017; Springer Nature B.V
• Subjects: Animals; Apoptosis; Calcium-Binding Proteins - metabolism; Cardiology; Cardiomyocytes; Cell Line; Cell signaling; Disease Models, Animal; Equivalence; Exercise Test; Extracellular Signal-Regulated MAP Kinases - metabolism; Extracellular vesicles; Extracellular Vesicles - metabolism; Extracellular Vesicles - transplantation; Flow cytometry; Flow Cytometry - methods; Growth factors; Heart; Heart diseases; HSP27 Heat-Shock Proteins - metabolism; Hsp27 protein; Humans; Hydrogen peroxide; Injection; Injuries; Insulin; Insulin-like growth factor I; Ischemia; Male; Medicine; Medicine & Public Health; Mice, Inbred C57BL; Myocardial Infarction - blood; Myocardial Infarction - pathology; Myocardial Infarction - prevention & control; Myocardial Reperfusion Injury - blood; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - prevention & control; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Nanotechnology - methods; Original Contribution; Oxidative Stress; Physical Conditioning, Animal - methods; Physical Exertion; Physical training; rab GTP-Binding Proteins - metabolism; Rats; Reperfusion; Rodents; Swimming; Time Factors; Vesicles; Extracellular vesicles; Ischemia–reperfusion injury; Exercise
• DOI: 10.1007/s00395-017-0628-z
• ISSN: 0300-8428; 1435-1803

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 H 2 O 2 -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.