Bei Yihua, Wang Hongyun, Liu Yang, Su Zhuhua, Li Xinpeng, Zhu Yujiao, Zhang Ziyi, Yin Mingming, Chen Chen, Li Lin, Wei Meng, Meng Xiangmin, Liang Xuchun, Huang Zhenzhen, Cao Richard Yang, Wang Lei, Li Guoping, Cretoiu Dragos, Xiao Junjie
Institute of Geriatrics ( Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong) and School of Life Science, Shanghai University, Nantong 226011, China.
Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education), Shanghai University, Shanghai 200444, China.
Research (Wash D C). 2024 Feb 26;7:0327. doi: 10.34133/research.0327. eCollection 2024.
Exercise can stimulate physiological cardiac growth and provide cardioprotection effect in ischemia/reperfusion (I/R) injury. MiR-210 is regulated in the adaptation process induced by exercise; however, its impact on exercise-induced physiological cardiac growth and its contribution to exercise-driven cardioprotection remain unclear. We investigated the role and mechanism of miR-210 in exercise-induced physiological cardiac growth and explored whether miR-210 contributes to exercise-induced protection in alleviating I/R injury. Here, we first observed that regular swimming exercise can markedly increase miR-210 levels in the heart and blood samples of rats and mice. Circulating miR-210 levels were also elevated after a programmed cardiac rehabilitation in patients that were diagnosed of coronary heart diseases. In 8-week swimming model in wild-type (WT) and miR-210 knockout (KO) rats, we demonstrated that miR-210 was not integral for exercise-induced cardiac hypertrophy but it did influence cardiomyocyte proliferative activity. In neonatal rat cardiomyocytes, miR-210 promoted cell proliferation and suppressed apoptosis while not altering cell size. Additionally, miR-210 promoted cardiomyocyte proliferation and survival in human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and AC16 cell line, indicating its functional roles in human cardiomyocytes. We further identified miR-210 target genes, cyclin-dependent kinase 10 (CDK10) and ephrin-A3 (EFNA3), that regulate cardiomyocyte proliferation and apoptosis. Finally, miR-210 KO and WT rats were subjected to swimming exercise followed by I/R injury. We demonstrated that miR-210 crucially contributed to exercise-driven cardioprotection against I/R injury. In summary, this study elucidates the role of miR-210, an exercise-responsive miRNA, in promoting the proliferative activity of cardiomyocytes during physiological cardiac growth. Furthermore, miR-210 plays an essential role in mediating the protective effects of exercise against cardiac I/R injury. Our findings suggest exercise as a potent nonpharmaceutical intervention for inducing miR-210, which can alleviate I/R injury and promote cardioprotection.
运动可以刺激生理性心脏生长，并在缺血/再灌注（I/R）损伤中发挥心脏保护作用。miR-210在运动诱导的适应过程中受到调控；然而，其对运动诱导的生理性心脏生长的影响及其对运动驱动的心脏保护作用的贡献仍不清楚。我们研究了miR-210在运动诱导的生理性心脏生长中的作用和机制，并探讨了miR-210是否有助于运动诱导的保护作用以减轻I/R损伤。在此，我们首先观察到，定期游泳运动可显著提高大鼠和小鼠心脏及血液样本中miR-210的水平。在被诊断为冠心病的患者进行程序性心脏康复后，循环miR-210水平也会升高。在野生型（WT）和miR-210基因敲除（KO）大鼠的8周游泳模型中，我们证明miR-210对于运动诱导的心脏肥大并非不可或缺，但它确实影响心肌细胞的增殖活性。在新生大鼠心肌细胞中，miR-210促进细胞增殖并抑制细胞凋亡，同时不改变细胞大小。此外，miR-210在人胚胎干细胞衍生的心肌细胞（hESC-CMs）和AC16细胞系中促进心肌细胞增殖和存活，表明其在人心肌细胞中的功能作用。我们进一步鉴定了miR-210的靶基因，细胞周期蛋白依赖性激酶10（CDK10）和ephrin-A3（EFNA3），它们调节心肌细胞增殖和凋亡。最后，对miR-210 KO和WT大鼠进行游泳运动，随后进行I/R损伤。我们证明miR-210在运动驱动的针对I/R损伤的心脏保护中起关键作用。总之，本研究阐明了运动反应性miRNA miR-210在生理性心脏生长过程中促进心肌细胞增殖活性的作用。此外，miR-210在介导运动对心脏I/R损伤的保护作用中起重要作用。我们的研究结果表明运动是一种有效的非药物干预措施，可诱导miR-210，从而减轻I/R损伤并促进心脏保护。
