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Circ Res:促进动脉粥样硬化斑块稳定新目标:抑制DNA损伤

2014-12-24 MedSci MedSci原创

DNA损伤是动脉粥样硬化特点之一,可见于早期损害中,随着疾病的发展而发展,在晚期斑块中非常普遍。血管平滑肌细胞、内皮细胞、巨噬细胞都显示核DNA和线粒体DNA损伤。DNA损伤在以上细胞中都会影响其正常功能,而血管平滑肌细胞可以显示持续的DNA损伤。DNA损伤激活DNA损伤应答反应,从而推迟细胞周期并促进DNA修复。DNA双链断裂在DNA损伤中非常普遍,促进MRN复合体DNA激活。 英国剑桥大

DNA损伤是动脉粥样硬化特点之一,可见于早期损害中,随着疾病的发展而发展,在晚期斑块中非常普遍。血管平滑肌细胞、内皮细胞、巨噬细胞都显示核DNA和线粒体DNA损伤。DNA损伤在以上细胞中都会影响其正常功能,而血管平滑肌细胞可以显示持续的DNA损伤。DNA损伤激活DNA损伤应答反应,从而推迟细胞周期并促进DNA修复。DNA双链断裂在DNA损伤中非常普遍,促进MRN复合体DNA激活。

英国剑桥大学Kelly Gray及其团队研究了动脉粥样硬化中DNA损伤对血管平滑肌的影响,并将研究成果发布在12月的circulation research上。
Tags:DNA损伤、动脉粥样硬化、凋亡

基本原理:动脉粥样硬化患者其血管平滑肌细胞中已经确认存在DNA损伤和损伤应答。虽然DNA双链断裂(DSBS)可能通过促进细胞衰老、凋亡和炎症,从而会促进斑块进展使得斑块稳定性下降,但是,DNA双链断裂在动脉粥样硬化形成中对血管平滑肌的直接作用仍旧是未知的。

目的:明确动脉粥样硬化血管平滑肌中的DNA双链断裂是否存在以及其内源性水平的影响。

方法和结果:体内和体外实验显示,DNA损伤应答在人动脉粥样硬化斑块血管平滑肌中表达增高,MRN复合物(MRE11, RAD50, NBS1)检测到DNA双链断裂修复。斑块血管平滑肌中,氧化应激诱导的DNA双链断裂增高,然而DNA双链断裂并没有得到修复。为了明确DNA双链断裂在动脉粥样硬化中的作用,用血管平滑肌中表达NBS1和C端删除的NBS1两种新型转基因鼠,将其与ApoE基因敲除(ApoE-/-)鼠杂交。SM22α-NBS1/ApoE-/-血管平滑肌显示DNA双链断裂修复增加,生长停滞和凋亡减少,SM22α-(ΔC)NBS1/ApoE-/-鼠显示DNA双链断裂修复下降,生长停滞和凋亡增加。加速或延缓DNA双链断裂修复并不影响动脉粥样硬化程度和组成。然而,血管平滑肌中DNA损伤会减少斑块纤维帽区域,相反的,促进DNA双链断裂修复会增加其区域和血管平滑肌含量。

结果:人动脉粥样硬化斑块血管平滑肌显示DNA损伤增加,包括DNA双链断裂和DNA损伤应答激活。血管平滑肌DNA损伤对动脉粥样硬化的影响很小,但是在损伤晚期,改变的斑块表型能够抑制纤维帽区域。在动脉粥样硬化中,抑制DNA损伤可能作为促进斑块稳定的新目标。


原始出处:

Gray KL, Kumar SV, Figg N, Harrison J, Baker L, Mercer JR, Littlewood TD, Bennett MR. Effects of DNA Damage in Smooth Muscle Cells in Atherosclerosis. Circulation research. 2014. Dec 18

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