微小RNA-210介导运动保护心肌缺血再灌注损伤的作用及分子机制

Exercise can induce physiological cardiac hypertrophy, and protect against myocardial ischemia-reperfusion injury (IRI). MicroRNA-210 (miR-210) is upregulated in exercised heart, however, whether it could mediate the protective effect of exercise against cardiac IRI remains unclear. We previously found that miR-210 knockout did not affect exercise-induced hypertrophy of cardiomyocytes, but did block exercise-induced proliferation of cardiomyocytes, which might influence the benefit of exercise in preventing cardiac IRI. In the current project, we aim first to investigate the functional roles of miR-210 on the hypertrophy, proliferation, and apoptosis of cardiomyocytes and to clarify the potential of miR-210 in exercise-induced physiological hypertrophy by using swimming model of miR-210 knockout rats. Second, we will establish swimming and IRI models in miR-210 knockout rats to clarify whether miR-210 upregulation is necessary for the protective effect of exercise against cardiac IRI. Also, we will subject miR-210 transgenic rats to IRI model and investigate whether overexpressing miR-210 could mimic the protective effect of exercise against IRI. Finally, based on our previously identified potential target gene of miR-210, CDK10-related function-rescue experiments will be conducted to unravel the molecular mechanism underlying the role of miR-210 mediating the benefit of exercise in preventing IRI. Indeed, miR-210 might serve as a key molecule mediating the protective effect of exercise against cardiac IRI.

运动诱导生理性心肌肥大，保护心肌缺血再灌注损伤（IRI）。微小RNA-210（miR-210）在运动心脏上调，但其是否介导运动保护IRI尚不清楚。我们前期研究发现：miR-210敲除不影响运动诱导心肌细胞肥大，但阻碍了运动诱导心肌细胞的增殖，这可能一定程度影响运动保护IRI的效应。在本项目中，我们拟首先明确miR-210对心肌细胞肥大、增殖和凋亡的影响；通过miR-210敲除大鼠游泳模型明确miR-210和生理性心肌肥大的关系。接着，运用miR-210敲除大鼠，游泳后构建IRI，明确miR-210是否是运动减轻IRI所必须；运用miR-210过表达大鼠IRI模型，明确miR-210上调可否模拟运动保护IRI。最后，基于我们已发现的miR-210潜在靶基因CDK10，通过功能逆转实验明确miR-210介导运动保护IRI的分子机制。miR-210可能成为一个介导运动保护IRI的关键分子。

运动可以诱导生理性心肌肥厚，保护心脏抵抗心肌缺血再灌注损伤（Ischemia-Reperfusion Injury，IRI）。微小RNA-210（miR-210）在运动心脏上调，但miR-210与运动诱导生理性心肌肥厚的关系及其是否介导运动减轻IRI的保护效应先前是未知的。本项目首先构建了大鼠游泳诱导生理性心肌肥厚的模型，miR-210敲除大鼠在游泳训练后心脏仍然发生体积增大、重量增加，心肌横截面积增大，但是游泳诱导心肌细胞增殖标记物表达增加的效应被消除，这说明miR-210是运动诱导心肌细胞增殖所必需，但不介导运动诱导心肌细胞生理性肥大的效应。接着，在新生大鼠心肌细胞水平，明确了miR-210不影响心肌细胞的面积，但可以促进心肌细胞的增殖，抑制氧葡萄糖剥夺恢复（OGDR）诱导心肌细胞的凋亡，并鉴定出CDK10和EFNA3是miR-210的下游靶基因。进一步，我们构建了大鼠游泳后诱导心肌IRI损伤的模型，运动训练可以减轻IRI，而miR-210敲除会消除运动的心肌保护效应，表现为心梗面积增大，心肌凋亡增加而增殖减弱。在IRI心脏组织中，运动训练可以降低CDK10和EFNA3的表达，而miR-210敲除会上调CDK10和EFNA3的表达，这说明miR-210在体内调控CDK10和EFNA3的表达，介导运动减轻IRI的保护效应。综上，本项目明确了miR-210和运动诱导生理性心肌肥厚的关系，鉴定出miR-210通过抑制靶基因CDK10和EFNA3，促进心肌细胞增殖、抑制心肌细胞凋亡的下游分子机制，揭示了miR-210介导运动减轻心肌IRI的保护效应，miR-210是一个介导运动保护IRI的关键分子。