Mettl14介导的m6A修饰对改善心肌梗死的分子机制  

Molecular mechanism of Mettl14 mediated m6A modification in improving myocardial infarction

作　　者：郑学斌[1] 沙莎[1] 杨慧琼 刘恋 ZHENG Xuebin;SHA Sha;YANG Huiqiong;LIU Lian(Department of General Practice,Changsha Fourth Hospital(Changsha Hospital Affiliated to Hunan Normal University),Changsha 410006,China)

机构地区：[1]长沙市第四医院(湖南师范大学附属长沙医院)全科医学科,长沙410006

出　　处：《实用医学杂志》2023年第21期2754-2760,共7页The Journal of Practical Medicine

基　　金：湖南省卫生健康委员会科研项目(编号:20210278)。

摘　　要：目的探索甲基转移酶样14(METTL14)介导的N6-甲基腺苷(m6A)修饰在心肌梗死(MI)中的生物学作用。方法将小鼠随机分为4组,每组10只:Sham+AAV9-NC组、Sham+AAV9-METTL14组、MI+AAV9-NC组和MI+AAV9-METTL14组。各组小鼠分别在MI诱导前1周将AAV9-METTL14或AAV9-NC通过尾静脉注射到小鼠体内。通过经胸超声心动图无创测量心脏功能,并采用免疫荧光测定小鼠微血管损伤和内皮线粒体功能障碍。从小鼠心肌组织中分离CMECs,对细胞进行去氧葡萄糖(OGD)处理。结果METTL14在MI小鼠心脏组织以及OGD处理的CMECs中下调。与Sham+AAV9-NC组小鼠相比,MI+AAV9-NC组小鼠中VE-cadherin表达显著下调(P<0.05),线粒体ROS水平显著增加(P<0.05)。MI+AAV9-METTL14抑制了这些变化,并增强了小鼠的心脏功能。与NC组相比,在OGD组CMECs细胞中观察到线粒体ROS水平显著增加(P<0.05)。CMECs细胞中METTL14敲低加剧了ROS水平(P<0.05),当加入USP48过表达质粒则逆转了这些变化(P<0.05)。结论METTL14在MI中低表达,并通过增加CMECs细胞USP48的m6A修饰水平以降低其稳定性,从而介导CMECs细胞线粒体功能障碍。Objective To investigate the biological role of methyltransferase-like 14(METTL14)-medi⁃ated m6A modification in myocardial infarction(MI).Methods A total of 40 mice were randomly divided into 4 groups:Sham+AAV9-NC group(n=10),Sham+AAV9-METTL14 group(n=10),MI+AAV9-NC group(n=10)and MI+AAV9-METTL14 group(n=10).Mice in each group were injected with AAV9-METTL14 or AAV9-NC through the tail vein one week before MI induction.Cardiac function was measured non-invasively by transthoracic echocardiography,and microvascular injury were measured by immunofluorescence.CMECs were isolated from mouse myocardial tissue,and the cells were treated with oxygen-glucose deprivation(OGD).Results METTL14 was downregulated in MI mouse heart tissue as well as in OGD-treated CMECs.Compared with the Sham+AAV9-NC group,the expression of VE-cadherin was significantly down-regulated(P<0.05),ROS levels increased signifi⁃cantly(P<0.05)in the MI+AAV9-NC group.MI+AAV9-METTL14 suppressed these changes and enhanced cardiac function in mice.Compared with the NC group,a significant increase in mitochondrial ROS levels was observed in the OGD group(P<0.05).Knockdown of METTL14 in CMECs exacerbated ROS levels(P<0.05),and the addition of USP48 overexpression plasmid reversed these changes(P<0.05).Conclusion METTL14 was lowly expressed in MI and mediates mitochondrial dysfunction in CMECs by increasing the m6A modification level of USP48 in CMECs to reduce its stability.

关 键 词：甲基转移酶样14 N6-甲基腺苷 心肌梗死 泛素特异性肽酶48 

分 类 号：R54[医药卫生—心血管疾病]