靶向载脂蛋白C3反而会加重患有严重难治性高胆固醇血症的仓鼠的动脉粥样硬化。
Targeting ApoC3 Paradoxically Aggravates Atherosclerosis in Hamsters With Severe Refractory Hypercholesterolemia.
作者信息
Xu Yitong, Guo Jiabao, Zhang Ling, Miao Guolin, Lai Pingping, Zhang Wenxi, Liu Lili, Hou Xinlin, Wang Yuhui, Huang Wei, Liu George, Gao Mingming, Xian Xunde
机构信息
Laboratory of Lipid Metabolism, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China.
Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, School of Basic Medical Sciences, Peking University, Beijing, China.
出版信息
Front Cardiovasc Med. 2022 Feb 2;9:840358. doi: 10.3389/fcvm.2022.840358. eCollection 2022.
RATIONALE
ApoC3 plays a central role in the hydrolysis process of triglyceride (TG)-rich lipoproteins mediated by lipoprotein lipase (LPL), which levels are positively associated with the incidence of cardiovascular disease (CVD). Although targeting ApoC3 by antisense oligonucleotide (ASO), Volanesorsen markedly reduces plasma TG level and increase high-density lipoprotein cholesterol (HDL-C) in patients with hypertriglyceridemia (HTG), the cholesterol-lowering effect of ApoC3 inhibition and then the consequential outcome of atherosclerotic cardiovascular disease (ASCVD) have not been reported in patients of familial hypercholesterolemia (FH) with severe refractory hypercholesterolemia yet.
OBJECTIVE
To investigate the precise effects of depleting ApoC3 on refractory hypercholesterolemia and atherosclerosis, we crossed ApoC3-deficient hamsters with a background of LDLR deficiency to generate a double knockout (DKO) hamster model (LDLR, XApoC3, DKO).
APPROACH AND RESULTS
On the standard laboratory diet, DKO hamsters had reduced levels of plasma TG and total cholesterol (TC) relative to LDLR hamsters. However, upon high-cholesterol/high-fat (HCHF) diet feeding for 12 weeks, ApoC3 deficiency reduced TG level only in female animals without affecting refractory cholesterol in the circulation, whereas apolipoprotein A1 (ApoA1) levels were significantly increased in DKO hamsters with both genders. Unexpectedly, loss of ApoC3 paradoxically accelerated diet-induced atherosclerotic development in female and male LDLR hamsters but ameliorated fatty liver in female animals. Further analysis of blood biological parameters revealed that lacking ApoC3 resulted in abnormal platelet (PLT) indices, which could potentially contribute to atherosclerosis in LDLR hamsters.
CONCLUSIONS
In this study, our novel findings provide new insight into the application of ApoC3 inhibition for severe refractory hypercholesterolemia and ASCVD.
原理
载脂蛋白C3（ApoC3）在脂蛋白脂肪酶（LPL）介导的富含甘油三酯（TG）的脂蛋白水解过程中起核心作用，其水平与心血管疾病（CVD）的发病率呈正相关。尽管通过反义寡核苷酸（ASO）靶向ApoC3的药物沃拉尼森可显著降低高甘油三酯血症（HTG）患者的血浆TG水平并提高高密度脂蛋白胆固醇（HDL-C）水平，但ApoC3抑制对家族性高胆固醇血症（FH）伴严重难治性高胆固醇血症患者的降胆固醇作用以及随后的动脉粥样硬化性心血管疾病（ASCVD）的相应结局尚未见报道。
目的
为了研究消耗ApoC3对难治性高胆固醇血症和动脉粥样硬化的确切影响，我们将ApoC3缺陷型仓鼠与低密度脂蛋白受体（LDLR）缺陷背景的仓鼠杂交，以生成双敲除（DKO）仓鼠模型（LDLR，XApoC3，DKO）。
方法与结果
在标准实验室饮食条件下，与LDLR仓鼠相比，DKO仓鼠的血浆TG和总胆固醇（TC）水平降低。然而，在高胆固醇/高脂肪（HCHF）饮食喂养12周后，ApoC3缺乏仅在雌性动物中降低了TG水平，而不影响循环中的难治性胆固醇，而在雌雄DKO仓鼠中载脂蛋白A1（ApoA1）水平均显著升高。出乎意料的是，ApoC3的缺失反而加速了雌性和雄性LDLR仓鼠饮食诱导的动脉粥样硬化发展，但改善了雌性动物的脂肪肝。对血液生物学参数的进一步分析表明，缺乏ApoC3导致血小板（PLT）指数异常，这可能是LDLR仓鼠动脉粥样硬化的潜在原因。
结论
在本研究中，我们的新发现为ApoC3抑制在严重难治性高胆固醇血症和ASCVD中的应用提供了新的见解。
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