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Upregulation of microRNA-532 enhances cardiomyocyte apoptosis in the diabetic heart.
Apoptosis ( IF 6.1 ) Pub Date : 2020-05-16 , DOI: 10.1007/s10495-020-01609-1
Dhananjie N K Chandrasekera 1 , Joshua P H Neale 1, 2 , Isabelle van Hout 1 , Shruti Rawal 1, 3 , Sean Coffey 4 , Gregory T Jones 5 , Richard Bunton 6 , Ramanen Sugunesegran 6 , Dominic Parry 6 , Philip Davis 6 , Patrick Manning 4 , Michael J A Williams 4 , Rajesh Katare 1
Affiliation  

Type 2 diabetes has a strong association with the development of cardiovascular disease, which is grouped as diabetic heart disease (DHD). DHD is associated with the progressive loss of cardiovascular cells through the alteration of molecular signalling pathways associated with cell death. In this study, we sought to determine whether diabetes induces dysregulation of miR-532 and if this is associated with accentuated apoptosis. RT-PCR analysis showed a significant increase in miR-532 expression in the right atrial appendage tissue of type 2 diabetic patients undergoing coronary artery bypass graft surgery. This was associated with marked downregulation of its anti-apoptotic target protein apoptosis repressor with caspase recruitment domain (ARC) and increased TUNEL positive cardiomyocytes. Further analysis showed a positive correlation between apoptosis and miR-532 levels. Time-course experiments in a mouse model of type 2 diabetes showed that diabetes-induced activation of miR-532 occurs in the later stage of the disease. Importantly, the upregulation of miR-532 preceded the activation of pro-apoptotic caspase-3/7 activity. Finally, inhibition of miR-532 activity in high glucose cultured human cardiomyocytes prevented the downregulation of ARC and attenuated apoptotic cell death. Diabetes induced activation of miR-532 plays a critical role in accelerating cardiomyocytes apoptosis. Therefore, miR-532 may serve as a promising therapeutic agent to overcome the diabetes-induced loss of cardiomyocytes.

中文翻译:

microRNA-532的上调增强了糖尿病心脏中心肌细胞的凋亡。

2型糖尿病与心血管疾病的发展密切相关,心血管疾病被归类为糖尿病性心脏病(DHD)。DHD通过改变与细胞死亡相关的分子信号通路,与心血管细胞的逐步丧失有关。在这项研究中,我们试图确定糖尿病是否诱导miR-532失调,以及是否与细胞凋亡加剧有关。RT-PCR分析显示,在进行冠状动脉搭桥术的2型糖尿病患者的右心耳附件组织中,miR-532表达显着增加。这与其具有caspase募集域(ARC)的抗凋亡靶蛋白凋亡抑制因子的明显下调和TUNEL阳性心肌细胞的增加有关。进一步分析显示凋亡与miR-532水平呈正相关。在2型糖尿病小鼠模型中进行的时程实验表明,糖尿病诱导的miR-532激活发生在疾病的晚期。重要的是,miR-532的上调先于凋亡前胱天蛋白酶3/7活性的激活。最后,在高葡萄糖培养的人心肌细胞中抑制miR-532活性可以防止ARC的下调,并减轻凋亡细胞的死亡。糖尿病引起的miR-532激活在加速心肌细胞凋亡中起关键作用。因此,miR-532可以作为克服糖尿病引起的心肌细胞丢失的有前途的治疗剂。在2型糖尿病小鼠模型中进行的时程实验表明,糖尿病诱导的miR-532激活发生在疾病的晚期。重要的是,miR-532的上调先于凋亡前胱天蛋白酶3/7活性的激活。最后,在高葡萄糖培养的人心肌细胞中抑制miR-532活性可以防止ARC的下调,并减轻凋亡细胞的死亡。糖尿病引起的miR-532激活在加速心肌细胞凋亡中起关键作用。因此,miR-532可以作为克服糖尿病引起的心肌细胞丢失的有前途的治疗剂。在2型糖尿病小鼠模型中进行的时程实验表明,糖尿病诱导的miR-532激活发生在疾病的晚期。重要的是,miR-532的上调先于凋亡前胱天蛋白酶3/7活性的激活。最后,在高葡萄糖培养的人心肌细胞中抑制miR-532活性可以防止ARC的下调,并减轻凋亡细胞的死亡。糖尿病引起的miR-532激活在加速心肌细胞凋亡中起关键作用。因此,miR-532可以作为克服糖尿病引起的心肌细胞丢失的有前途的治疗剂。高糖培养的人心肌细胞中miR-532活性的抑制阻止了ARC的下调并减轻了凋亡细胞的死亡。糖尿病引起的miR-532激活在加速心肌细胞凋亡中起关键作用。因此,miR-532可作为克服糖尿病引起的心肌细胞丢失的有前途的治疗剂。高糖培养的人心肌细胞中miR-532活性的抑制阻止了ARC的下调并减轻了凋亡细胞的死亡。糖尿病引起的miR-532激活在加速心肌细胞凋亡中起关键作用。因此,miR-532可作为克服糖尿病引起的心肌细胞丢失的有前途的治疗剂。
更新日期:2020-05-16
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