From the School of Aerospace Medicine (Z.H., X.Q., Y.H., X.Z., G.L., J.W., J.L., F.G.), Fourth Military Medical University, Xi'an, China.
Department of Physical Education (J.S.), Fourth Military Medical University, Xi'an, China.
Circ Res. 2019 Apr 26;124(9):1386-1400. doi: 10.1161/CIRCRESAHA.118.314635.
Exercise training, in addition to reducing cardiovascular risk factors, confers direct protection against myocardial ischemia/reperfusion injury and has been associated with improved heart attack survival in humans. However, the underlying mechanisms of exercise-afforded cardioprotection are still unclear.
To investigate the role of exercise-derived circulating exosomes in cardioprotection and the molecular mechanisms involved.
Circulating exosomes were isolated from the plasma of volunteers with or without exercise training and rats subjected to 4-week swim exercise or sedentary littermates 24 hours after the last training session. Although the total circulating exosome level did not change significantly in exercised subjects 24 hours post-exercise compared with the sedentary control, the isolated plasma exosomes from exercised rats afforded remarkable protection against myocardial ischemia/reperfusion injury. miRNA sequencing combined with quantitative reverse transcription polymerase chain reaction validation identified 12 differentially expressed miRNAs from the circulating exosomes of exercised rats, among which miR-342-5p stood out as the most potent cardioprotective molecule. Importantly, the cardioprotective effects and the elevation of exosomal miR-342-5p were also observed in exercise-trained human volunteers. Moreover, inhibition of miR-342-5p significantly blunted the protective effects of exercise-derived circulating exosomes in hypoxia/reoxygenation cardiomyocytes; in vivo cardiac-specific inhibition of miR-342-5p through serotype 9 adeno-associated virus-mediated gene delivery attenuated exercise-afforded cardioprotection in myocardial ischemia/reperfusion rats. Mechanistically, miR-342-5p inhibited hypoxia/reoxygenation-induced cardiomyocyte apoptosis via targeting Caspase 9 and Jnk2; it also enhanced survival signaling (p-Akt) via targeting phosphatase gene Ppm1f. Of note, exercise training or laminar shear stress directly enhanced the synthesis of miR-342-5p in endothelial cells.
Our findings reveal a novel endogenous cardioprotective mechanism that long-term exercise-derived circulating exosomes protect the heart against myocardial ischemia/reperfusion injury via exosomal miR-342-5p.
运动训练除了降低心血管危险因素外，还能直接对抗心肌缺血/再灌注损伤，并与人类心脏病发作存活率的提高相关。然而，运动带来的心脏保护的潜在机制仍不清楚。
研究运动衍生的循环外泌体在心脏保护中的作用及其涉及的分子机制。
从有或没有运动训练的志愿者和经过 4 周游泳运动或久坐不动的同窝大鼠的血浆中分离循环外泌体，最后一次训练后 24 小时。虽然与久坐不动的对照组相比，运动后 24 小时受试者的总循环外泌体水平没有明显变化，但运动大鼠分离的血浆外泌体对心肌缺血/再灌注损伤有显著的保护作用。miRNA 测序结合定量逆转录聚合酶链反应验证从运动大鼠的循环外泌体中鉴定出 12 个差异表达的 miRNA，其中 miR-342-5p 是最有效的心脏保护分子。重要的是，在运动训练的人类志愿者中也观察到了这种心脏保护作用和外泌体 miR-342-5p 的升高。此外，miR-342-5p 的抑制显著减弱了运动衍生的循环外泌体在缺氧/复氧心肌细胞中的保护作用；通过血清型 9 腺相关病毒介导的基因传递在体内特异性抑制 miR-342-5p 可减弱心肌缺血/再灌注大鼠的运动带来的心脏保护作用。在机制上，miR-342-5p 通过靶向 Caspase 9 和 Jnk2 抑制缺氧/复氧诱导的心肌细胞凋亡；它还通过靶向磷酸酶基因 Ppm1f 增强存活信号（p-Akt）。值得注意的是，运动训练或层流剪切力直接增强了内皮细胞中 miR-342-5p 的合成。
我们的研究结果揭示了一种新的内源性心脏保护机制，即长期运动衍生的循环外泌体通过外泌体 miR-342-5p 保护心脏免受心肌缺血/再灌注损伤。
