血浆 PCSK9 水平升高对非家族性高胆固醇血症和杂合子家族性高胆固醇血症患者同样有害，与低密度脂蛋白受体缺陷无关。
Elevated plasma PCSK9 level is equally detrimental for patients with nonfamilial hypercholesterolemia and heterozygous familial hypercholesterolemia, irrespective of low-density lipoprotein receptor defects.
机构信息
Faculté de Médecine, Université de Nantes, UMR PhAN 1280, Nantes, France; Lipid Research Group, Heart Research Institute, Sydney, Australia.
Lipid Research Group, Heart Research Institute, Sydney, Australia; Centre for Vascular Research, University of New South Wales, Sydney, Australia.
出版信息
J Am Coll Cardiol. 2014 Jun 10;63(22):2365-73. doi: 10.1016/j.jacc.2014.02.538. Epub 2014 Mar 12.
OBJECTIVES
Do elevated proprotein convertase subtilisin/kexin type 9 (PCSK9) levels constitute an even greater risk for patients who already have reduced low-density lipoprotein receptor (LDLR) levels, such as those with heterozygous familial hypercholesterolemia (HeFH)?
BACKGROUND
As a circulating inhibitor of LDLR, PCSK9 is an attractive target for lowering LDL-cholesterol (LDL-C) levels.
METHODS
Circulating PCSK9 levels were measured by enzyme-linked immunosorbent assay in nontreated patients with HeFH carrying a D206E (n = 237), V408M (n = 117), or D154N (n = 38) LDLR missense mutation and in normolipidemic controls (n = 152). Skin fibroblasts and lymphocytes were isolated from a subset of patients and grown in 0.5% serum and mevastatin with increasing amounts of recombinant PCSK9. LDLR abundance at the cell surface was determined by flow cytometry.
RESULTS
PCSK9 reduced LDLR expression in a dose-dependent manner in control and FH fibroblasts to similar extents, by up to 77 ± 8% and 82 ± 7%, respectively. Likewise, PCSK9 reduced LDLR abundance by 39 ± 8% in nonfamilial hypercholesterolemia (non-FH) and by 45 ± 10% in HeFH lymphocytes, irrespective of their LDLR mutation status. We found positive correlations of the same magnitude between PCSK9 and LDL-C levels in controls (beta = 0.22; p = 0.0003), D206E (beta = 0.20; p = 0.0002), V408M (beta = 0.24; p = 0.0002), and D154N (beta = 0.25; p = 0.048) patients with HeFH. The strengths of these associations were all similar.
CONCLUSIONS
Elevated PCSK9 levels are equally detrimental for patients with HeFH or non-FH: a 100-ng/ml increase in PCSK9 will lead to an increase in LDL-C of 0.20 to 0.25 mmol/l in controls and HeFH alike, irrespective of their LDLR mutation. This explains why patients with non-FH or HeFH respond equally well to monoclonal antibodies targeting PCSK9.
目的
对于已经存在低密度脂蛋白受体 (LDLR) 水平降低的患者（如杂合子家族性高胆固醇血症 [HeFH] 患者），升高的前蛋白转化酶枯草溶菌素 9 (PCSK9) 水平是否构成更大的风险？
背景
作为 LDLR 的循环抑制剂，PCSK9 是降低 LDL-胆固醇 (LDL-C) 水平的一个有吸引力的靶点。
方法
通过酶联免疫吸附试验测量未经治疗的携带 D206E（n = 237）、V408M（n = 117）或 D154N（n = 38）LDLR 错义突变的 HeFH 患者和正常血脂对照者（n = 152）的循环 PCSK9 水平。从一部分患者中分离出皮肤成纤维细胞和淋巴细胞，并在 0.5%血清和洛伐他汀中培养，同时添加不同量的重组 PCSK9。通过流式细胞术测定细胞表面 LDLR 的丰度。
结果
PCSK9 以剂量依赖性方式降低对照和 FH 成纤维细胞中 LDLR 的表达，分别高达 77±8%和 82±7%。同样，PCSK9 使非家族性高胆固醇血症 (non-FH) 的 LDLR 丰度降低 39±8%，HeFH 淋巴细胞降低 45±10%，而与 LDLR 突变状态无关。我们发现对照者（β=0.22；p=0.0003）、D206E 患者（β=0.20；p=0.0002）、V408M 患者（β=0.24；p=0.0002）和 D154N 患者（β=0.25；p=0.048）中 PCSK9 与 LDL-C 水平之间存在相同幅度的正相关。这些关联的强度都相似。
结论
升高的 PCSK9 水平对 HeFH 或非 FH 患者同样有害：PCSK9 增加 100ng/ml，对照者和 HeFH 患者的 LDL-C 分别增加 0.20 至 0.25mmol/L，而与 LDLR 突变无关。这解释了为什么非 FH 或 HeFH 患者对靶向 PCSK9 的单克隆抗体同样有良好的反应。
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