Omega-3脂肪酸通过上调miR-210对心肌梗死后细胞凋亡的保护作用及机制研究

Myocardial ischemia after acute myocardial infarction（AMI）can lead to myocardial apoptosis, which is closely related to the prognosis of the patient. In the United States and Europe, the cardiovascular disease guidelines recommended taking omega-3 fatty acids to prevent sudden cardiac death after AMI, but the evidence level is not high (IIB). To address this clinical problems and provide a theoretical basis for nutrition interventions in patients with AMI, the fat-1 transgenic mice (with a high level of omega-3 fatty acids) were taken. Early animal studies found that omega-3 fatty acids can reduce myocardial apoptosis and protect the heart function through upregulating the expression of myocardial miRNA-210 after AMI. Bioinformatics prompte that CASP8AP2 is the target gene of miR-210, and CASP8AP2 is involved in the regulation of apoptosis. This study is designed on the basis of the preliminary study, to prove that omega-3 fatty acid can up-regulate miR-210 targeted CASP8AP2 to inhibit myocardial apoptosis though the pathway of “omega-3/ miRNA-210/ CASP8AP2”. This research may provide the theoretical basis for nutrition intervention in patients with AMI.

急性心肌梗死（AMI）后心肌缺血可导致心肌细胞凋亡，细胞凋亡的程度与病人的预后密切相关。尽管美国和欧洲心血管病指南均推荐AMI患者常规服用omega-3脂肪酸来预防猝死的发生，但证据等级不高（IIB级）。为了解决这一临床难题，为AMI患者的营养学干预提供理论依据，本课题利用fat-1转基因小鼠（高表达omega-3脂肪酸）进行研究。前期动物实验发现omega-3脂肪酸通过上调梗死心肌组织miRNA-210的表达水平进而减少AMI后心肌细胞凋亡，保护心功能。生物信息学提示CASP8AP2是miR-210的靶基因，CASP8AP2参与调控细胞凋亡。本项目拟在前期研究的基础上，通过“omega-3/ miRNA-210/ CASP8AP2”途径验证omega-3脂肪酸通过上调miRNA-210靶向CASP8AP2抑制心肌细胞的凋亡这一假说。通过本项目研究，可为AMI患者的营养学干预提供理论依据。

心肌梗死后1周，Fat-1转基因小鼠较WT小鼠有更好的心功能、更小的纤维化面积和更少的心肌凋亡细胞。MI后分析显示，与WT组相比，FAT-1转基因小鼠组有33个miRNAs显著上调，35个miRNAs下调。与WT小鼠相比，Fat-1转基因小鼠在选定的凋亡相关miRNAs中，9个miRNAs表达上调(miR-101A-3p，miR-128-3p，miR-133a-5p，miR-149-5p，miR-192-5p，miR-1a-3p，miR-208A-3p，miR-29c-5p，miR-30c-2-3p)， 3个miRNAs的表达下调(miR-210-3p，miR-21a-3p，miR-214-3p)。KEGG通路分析表明这些miRNAs在心肌梗死中可能发挥作用。此外，与WT相比，心肌梗死后Fat-1转基因小鼠心脏Bcl-2的表达增加，caspase-3的表达降低。.结论：. ω-3PUFA可调节心肌梗死后凋亡相关的miRNAs和靶基因的表达，进而对心梗后心肌细胞具有保护作用。