Heparin Does Not Regulate Circulating Human PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) in a General Population-Brief Report.
Heparin Does Not Regulate Circulating Human PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) in a General Population-Brief Report.
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在一般人群简要报告中，肝素不调节循环人类 PCSK9（前蛋白转化酶枯草杆菌蛋白酶-Kexin 9 型）。
DOI：
10.1161/atvbaha.122.318556
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Chorba,JohnS
中科院分区：
文献类型：
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作者：
Xia,VivianQ;Ong,ChuiMei;Zier,LucasS;MacGregor,JohnS;Wu,AlanHB;Chorba,JohnS
背景PCSK9（前蛋白转化酶枯草杆菌蛋白酶-kexin 9 型）陪伴肝脏 LDLR（低密度脂蛋白受体）进行溶酶体降解，提高血清 LDL（低密度脂蛋白）胆固醇并促进动脉粥样硬化性心脏病。虽然对肝脏 LDLR 的主要影响来自分泌的 PCSK9，但 PCSK9 重新摄取到肝细胞中的细节仍不清楚。在组织培养和动物模型中，肝细胞上的 HSPG（硫酸乙酰肝素蛋白聚糖）充当辅助受体，促进 PCSK9 的再摄取。我们假设，如果这种 PCSK9:HSPG 相互作用对人类很重要，那么用普通肝素 (UFH) 破坏它会急剧取代肝脏中的 PCSK9 并增加血浆 PCSK9。 方法我们从 160 名在静脉注射 UFH 之前和之后接受心导管插入术的受试者中获得了残余血浆样本。使用商业酶联免疫吸附测定法测定 PCSK9 水平。结果 UFH 之前血浆 PCSK9 中位数为 113 ng/mL，之后为 119 ng/mL。这种差异并不显着（P=0.83 [95% CI，-6.23 至 6.31 ng/mL]）。等效性测试提供了 95% 的置信度，表明 UFH 不会使血浆 PCSK9 升高 > 4.7%。在所有亚组中，只有基线 PCSK9 浓度最低的受试者表现出对 UFH 的反应（增加 8.8%，调整后 P=0.044）。在基线血浆 PCSK9 和 UFH 引起的血浆 PCSK9 变化之间观察到适度的相关性 (RS=-0.3634；P<0.0001)。 结论 在未选择的人类人群中，施用 UFH 不会对循环 PCSK9 产生具有临床意义的影响。结果对破坏 PCSK9:HSPG 相互作用作为 PCSK9 抑制的一般治疗策略的临床效用产生了怀疑。然而，观察结果表明，在选定的人群中，破坏 PCSK9:HSPG 相互作用仍可能影响 PCSK9 的再摄取并提供治疗益处。
BackgroundPCSK9 (proprotein convertase subtilisin-kexin type 9) chaperones the hepatic LDLR (low-density lipoprotein receptor) for lysosomal degradation, elevating serum LDL (low-density lipoprotein) cholesterol and promoting atherosclerotic heart disease. Though the major effect on the hepatic LDLR comes from secreted PCSK9, the details of PCSK9 reuptake into the hepatocyte remain unclear. In both tissue culture and animal models, HSPGs (heparan sulfate proteoglycans) on hepatocytes act as co-receptors to promote PCSK9 reuptake. We hypothesized that if this PCSK9:HSPG interaction is important in humans, disrupting it with unfractionated heparin (UFH) would acutely displace PCSK9 from the liver and increase plasma PCSK9.MethodsWe obtained remnant plasma samples from 160 subjects undergoing cardiac catheterization before and after administration of intravenous UFH. PCSK9 levels were determined using a commercial enzyme-linked immunosorbent assay.ResultsMedian plasma PCSK9 was 113 ng/mL prior to UFH and 119 ng/mL afterward. This difference was not significant (P=0.83 [95% CI, −6.23 to 6.31 ng/mL]). Equivalence testing provided 95% confidence that UFH would not raise plasma PCSK9 by > 4.7%. Among all subgroups, only subjects with the lowest baseline PCSK9 concentrations exhibited a response to UFH (8.8% increase, adj.P=0.044). A modest correlation was observed between baseline plasma PCSK9 and the change in plasma PCSK9 due to UFH (RS=−0.3634;P<0.0001).ConclusionsAdministration of UFH does not result in a clinically meaningful effect on circulating PCSK9 among an unselected population of humans. The results cast doubt on the clinical utility of disrupting the PCSK9:HSPG interaction as a general therapeutic strategy for PCSK9 inhibition. However, the observations suggest that in selected populations, disrupting the PCSK9:HSPG interaction could still affect PCSK9 reuptake and offer a therapeutic benefit.