Peled Michael, Nishi Hitoo, Weinstock Ada, Barrett Tessa J, Zhou Felix, Quezada Alexandra, Fisher Edward A
Department of Medicine, Leon H. Charney Division of Cardiology, and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York, United States of America.
PLoS One. 2017 Mar 14;12(3):e0173975. doi: 10.1371/journal.pone.0173975. eCollection 2017.
Atherosclerosis can be induced by the injection of a gain-of-function mutant of proprotein convertase subtilisin/kexin type 9 (PCSK9)-encoding adeno-associated viral vector (AAVmPCSK9), avoiding the need for knockout mice models, such as low-density lipoprotein receptor deficient mice. As regression of atherosclerosis is a crucial therapeutic goal, we aimed to establish a regression model based on AAVmPCSK9, which will eliminate the need for germ-line genetic modifications. C57BL6/J mice were injected with AAVmPCSK9 and were fed with Western diet for 16 weeks, followed by reversal of hyperlipidemia by a diet switch to chow and treatment with a microsomal triglyceride transfer protein inhibitor (MTPi). Sixteen weeks following AAVmPCSK9 injection, mice had advanced atherosclerotic lesions in the aortic root. Surprisingly, diet switch to chow alone reversed hyperlipidemia to near normal levels, and the addition of MTPi completely normalized hyperlipidemia. A six week reversal of hyperlipidemia, either by diet switch alone or by diet switch and MTPi treatment, was accompanied by regression of atherosclerosis as defined by a significant decrease of macrophages in the atherosclerotic plaques, compared to baseline. Thus, we have established an atherosclerosis regression model that is independent of the genetic background.
通过注射编码前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）的功能获得性突变体腺相关病毒载体（AAVmPCSK9）可诱发动脉粥样硬化，无需使用基因敲除小鼠模型，如低密度脂蛋白受体缺陷小鼠。由于动脉粥样硬化的消退是一个关键的治疗目标，我们旨在建立一个基于AAVmPCSK9的消退模型，这将消除对种系基因改造的需求。给C57BL6/J小鼠注射AAVmPCSK9，并给予西式饮食16周，然后通过改为普通饮食和用微粒体甘油三酯转移蛋白抑制剂（MTPi）治疗来逆转高脂血症。注射AAVmPCSK9 16周后，小鼠主动脉根部出现了进展性动脉粥样硬化病变。令人惊讶的是，仅改为普通饮食就将高脂血症逆转至接近正常水平，添加MTPi则使高脂血症完全恢复正常。单独通过饮食转换或通过饮食转换和MTPi治疗实现的六周高脂血症逆转，伴随着动脉粥样硬化的消退，与基线相比，动脉粥样硬化斑块中的巨噬细胞显著减少。因此，我们建立了一个与遗传背景无关的动脉粥样硬化消退模型。
