Department of Cell Biology, State University of New York Downstate Health Sciences University, Brooklyn, New York, USA; Department of Emergency, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Department of Cell Biology, State University of New York Downstate Health Sciences University, Brooklyn, New York, USA; Beijing University of Chinese Medicine, Beijing, China.
Atherosclerosis. 2021 May;324:9-17. doi: 10.1016/j.atherosclerosis.2021.03.011. Epub 2021 Mar 13.
Atherosclerosis progression and regression studies are related to its prevention and treatment. Although we have gained extensive knowledge on germline phospholipid transfer protein (PLTP) deficiency, the effect of inducible PLTP deficiency in atherosclerosis remains unexplored.
We generated inducible PLTP (iPLTP)-knockout (KO) mice and measured their plasma lipid levels after feeding a normal chow or a Western-type diet. Adenovirus associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9) was used to induce hypercholesterolemia in the mice. Collars were placed around the common carotid arteries, and atherosclerosis progression and regression in the carotid arteries and aortic roots were evaluated.
On a normal chow diet, iPLTP-KO mice exhibited decreased cholesterol, phospholipid, apoA-I, and apoB levels compared with control mice. Furthermore, the overall amount of high-density lipoprotein (HDL) particles was reduced in these mice, but this effect was more profound for larger HDL particles. On a Western-type diet, iPLTP-KO mice again exhibited reduced levels of all tested lipids, even though the basal lipid levels were increased. Additionally, these mice displayed significantly reduced atherosclerotic plaque sizes with increased plaque stability. Importantly, inducible PLTP deficiency significantly ameliorated atherosclerosis by reducing the size of established plaques and the number of macrophages in the plaques without causing lipid accumulation in the liver.
Induced PLTP deficiency in adult mice reduces plasma total cholesterol and triglycerides, prevents atherosclerosis progression, and promotes atherosclerosis regression. Thus, PLTP inhibition is a promising therapeutic approach for atherosclerosis.
动脉粥样硬化的进展和消退研究与动脉粥样硬化的预防和治疗有关。虽然我们对种系磷脂转移蛋白（PLTP）缺乏症有了广泛的了解，但诱导型 PLTP 缺乏症对动脉粥样硬化的影响仍未得到探索。
我们生成了诱导型 PLTP（iPLTP）敲除（KO）小鼠，并在喂食正常饲料或西式饮食后测量其血浆脂质水平。腺相关病毒-前蛋白转化酶枯草杆菌蛋白酶/凝血酶 9（AAV-PCSK9）用于诱导小鼠发生高胆固醇血症。在颈总动脉周围放置颈圈，评估颈动脉和主动脉根部的动脉粥样硬化进展和消退。
在正常饲料饮食中，与对照组小鼠相比，iPLTP-KO 小鼠的胆固醇、磷脂、载脂蛋白 A-I 和载脂蛋白 B 水平降低。此外，这些小鼠的高密度脂蛋白（HDL）颗粒总量减少，但大 HDL 颗粒的这种作用更为明显。在西式饮食中，iPLTP-KO 小鼠再次表现出所有测试脂质水平降低，尽管基础脂质水平升高。此外，这些小鼠的动脉粥样硬化斑块大小显著减小，斑块稳定性增加。重要的是，诱导型 PLTP 缺乏通过减少已形成斑块的大小和斑块中巨噬细胞的数量，而不引起肝脏脂质积累，显著改善了动脉粥样硬化。
成年小鼠中诱导型 PLTP 缺乏可降低血浆总胆固醇和甘油三酯，预防动脉粥样硬化进展，并促进动脉粥样硬化消退。因此，PLTP 抑制是动脉粥样硬化的一种有前途的治疗方法。
