Silbernagel Günther, Chen Yan Q, Li Hongxia, Lemen Deven, Wen Yi, Zhen Eugene Y, Rief Martin, Kleber Marcus E, Delgado Graciela E, Sarzynski Mark A, Qian Yue-Wei, Schmidt Boerge, Erbel Raimund, Trampisch Ulrike S, Moissl Angela P, Rudolf Henrik, Schunkert Heribert, Stang Andreas, März Winfried, Trampisch Hans J, Scharnagl Hubert, Konrad Robert J
Division of Angiology, Department of Internal Medicine (G.S.), Medical University of Graz, Austria.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (Y.Q.C., H.L., D.L., Y.W., E.Y.Z., Y.Q., R.J.K.).
Circulation. 2025 Jan 21;151(3):218-234. doi: 10.1161/CIRCULATIONAHA.124.069272. Epub 2024 Oct 11.
ANGPTL3/4/8 (angiopoietin-like proteins 3, 4, and 8) are important regulators of LPL (lipoprotein lipase). ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4. ANGPTL4/8 complex formation converts ANGPTL4 from a furin substrate to a plasmin substrate, and both cleavages generate similar C-terminal domain-containing (CD)-ANGPTL4 fragments. Whereas several studies have investigated associations of free ANGPTL proteins with cardiovascular risk, there are no data describing associations of the complexes and CD-ANGPTL4 with outcomes or describing the effects of the complexes on LPL bound to GPIHBP1 (glycosylphosphatidylinositol HDL-binding protein 1).
Recombinant protein assays were used to study ANGPTL protein and complex effects on GPIHBP1-LPL activity. ANGPTL3/8, ANGPTL3, ANGPTL4/8, and CD-ANGPTL4 were measured with dedicated immunoassays in 2394 LURIC (Ludwigshafen Risk and Cardiovascular Health) study participants undergoing coronary angiography and 6188 getABI study (German Epidemiological Trial on Ankle Brachial Index) participants undergoing ankle brachial index measurement. There was a follow-up for cardiovascular death with a median (interquartile range) duration of 9.80 (8.75-10.40) years in the LURIC study and 7.06 (7.00-7.14) years in the getABI study.
ANGPTL3/8 potently inhibited GPIHBP1-LPL activity and showed positive associations with LDL-C (low-density lipoprotein cholesterol) and triglycerides (both <0.001). However, in neither study did ANGPTL3/8 correlate with cardiovascular death. Free ANGPTL3 was positively associated with cardiovascular death in the getABI study but not the LURIC study. ANGPTL4/8 and especially CD-ANGPTL4 were positively associated with the prevalence of diabetes, CRP (C-reactive protein; all <0.001), and cardiovascular death in both studies. In the LURIC and getABI studies, respective hazard ratios for cardiovascular mortality comparing the third with the first ANGPTL4/8 tertile were 1.47 (1.15-1.88) and 1.68 (1.25-2.27) when adjusted for sex, age, body mass index, and diabetes. For CD-ANGPTL4, these hazard ratios were 2.44 (1.86-3.20) and 2.76 (2.00-3.82).
ANGPTL3/8 potently inhibited GPIHBP1-LPL enzymatic activity, consistent with its positive association with serum lipids. However, ANGPTL3/8, LDL-C, and triglyceride levels were not associated with cardiovascular death in the LURIC and getABI cohorts. In contrast, concentrations of ANGPTL4/8 and particularly CD-ANGPTL4 were positively associated with inflammation, the prevalence of diabetes, and cardiovascular mortality.
血管生成素样蛋白3/4/8（ANGPTL3/4/8）是脂蛋白脂肪酶（LPL）的重要调节因子。ANGPTL8与ANGPTL3和ANGPTL4形成复合物。ANGPTL4/8复合物的形成将ANGPTL4从弗林蛋白酶底物转变为纤溶酶底物，且两种切割均产生相似的含C末端结构域（CD）的ANGPTL4片段。尽管有多项研究调查了游离ANGPTL蛋白与心血管风险的关联，但尚无数据描述这些复合物及CD-ANGPTL4与预后的关联，也没有描述这些复合物对与糖基磷脂酰肌醇高密度脂蛋白结合蛋白1（GPIHBP1）结合的LPL的影响。
采用重组蛋白测定法研究ANGPTL蛋白及复合物对GPIHBP1-LPL活性的影响。在2394名接受冠状动脉造影的LURIC（路德维希港风险与心血管健康）研究参与者和6188名接受踝臂指数测量的getABI研究（德国踝臂指数流行病学试验）参与者中，使用专用免疫测定法检测ANGPTL3/8、ANGPTL3、ANGPTL4/8和CD-ANGPTL4。LURIC研究中心血管死亡的随访中位（四分位间距）时长为9.80（8.75 - 10.40）年，getABI研究中为7.06（7.00 - 7.14）年。
ANGPTL3/8强烈抑制GPIHBP1-LPL活性，并与低密度脂蛋白胆固醇（LDL-C）和甘油三酯呈正相关（两者均P<0.001）。然而，在两项研究中，ANGPTL3/8均与心血管死亡无相关性。在getABI研究中游离ANGPTL3与心血管死亡呈正相关，但在LURIC研究中并非如此。在两项研究中，ANGPTL4/8尤其是CD-ANGPTL4与糖尿病患病率、C反应蛋白（CRP；均P<0.001）及心血管死亡呈正相关。在LURIC和getABI研究中，在对性别、年龄、体重指数和糖尿病进行校正后，ANGPTL4/8三分位数最高组与最低组相比，心血管死亡的风险比分别为1.47（1.15 - 1.88）和1.68（1.25 - 2.27）。对于CD-ANGPTL4，这些风险比分别为2.44（1.86 - 3.20）和2.76（2.00 - 3.82）。
ANGPTL3/8强烈抑制GPIHBP1-LPL酶活性，与其与血脂的正相关一致。然而，在LURIC和getABI队列中，ANGPTL3/8、LDL-C和甘油三酯水平与心血管死亡无关。相反，ANGPTL4/8尤其是CD-ANGPTL4的浓度与炎症、糖尿病患病率及心血管死亡率呈正相关。
