循环中弗林蛋白酶切割的前蛋白转化酶枯草杆菌蛋白酶/克新9型浓度可预测日本受试者未来的冠状动脉事件。

Circulating Furin-Cleaved Proprotein Convertase Subtilisin/Kexin Type 9 Concentration Predicts Future Coronary Events in Japanese Subjects.

作者信息

Kataoka Yu, Harada-Shiba Mariko, Hori Mika, Watanabe Makoto, Kokubo Yoshihiro, Noguchi Teruo, Yasuda Satoshi, Miyamoto Yoshihiro

机构信息

Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.

Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center, Research Institute, Suita, Osaka, Japan.

出版信息

JACC Asia. 2021 Nov 23;1(3):360-368. doi: 10.1016/j.jacasi.2021.09.003. eCollection 2021 Dec.

DOI:10.1016/j.jacasi.2021.09.003

PMID:36341208

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9627806/

Abstract

BACKGROUND

Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates as mature and furin-cleaved forms, which differ in their properties to degrade low-density lipoprotein (LDL) receptors.

OBJECTIVES

In this study, we sought to investigate whether PCSK9 subtypes associate with atherosclerotic cardiovascular events.

METHODS

We investigated 1,436 statin-naive Japanese subjects without any cardiovascular disease in the Suita Study, an epidemiologic Japanese cohort study. Total, mature, and furin-cleaved PCSK9 levels were measured by means of enzyme-linked immunosorbent assay. The occurrence of coronary and stroke events were compared in subjects stratified by PCSK9 level tertile.

RESULTS

Total, mature, and furin-cleaved PCSK9 levels were associated with non-high-density lipoprotein cholesterol (all < 0.001) and systolic blood pressure ( = 0.001, = 0.004, and < 0.001, respectively). Furthermore, only furin-cleaved PCSK9 level was correlated to high-sensitivity C-reactive protein (hs-CRP) ( < 0.001). During the 13.6-year observational period, furin-cleaved PCSK9 level predicted a greater likelihood of experiencing coronary events (tertile 2: hazard ratio [HR]: 2.84 [95% confidence interval [CI]: 1.21-6.65; = 0.01]; tertile 3: HR: 2.81 [95% CI: 1.17-6.74; = 0.02]), but not stroke (tertile 2: HR: 1.31 [95% CI: 0.72-2.40; = 0.36]; tertile 3: HR: 1.27 [95% CI: 0.68-2.38; = 0.44]). Total and mature PCSK9 levels were not associated with coronary events (total PCSK9: tertile 2: HR: 1.35 [95% CI: 0.68-2.68; = 0.39]; tertile 3: HR: 1.13 [95% CI: 0.54-2.34; = 0.73]; mature PCSK9: tertile 2: HR: 1.02 [95% CI: 0.52-2.02; = 0.93]; tertile 3: HR: 0.96 [95% CI: 0.47-1.95; = 0.92]) and stroke events (total PCSK9: tertile 2: HR: 0.90 [95% CI: 0.50-1.61; = 0.72]; tertile 3: HR: 0.99 [95% CI:0.54-1.80; = 0.97]; mature PCSK9: tertile 2: HR: 0.86 [95% CI: 0.47-1.57; = 0.63]; tertile 3: HR: 1.11 [95% CI: 0.61-1.99; = 0.72]), respectively.

CONCLUSIONS

Furin-cleaved but not total and mature PCSK9 was associated with both LDL cholesterol and hs-CRP and predicted future coronary events in the primary prevention settings. Our findings provide pathophysiological insights into the properties of PCSK9 subtypes in association with coronary events.

摘要

背景

前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）以成熟形式和经弗林蛋白酶切割的形式在血液中循环，它们在降解低密度脂蛋白（LDL）受体的特性上有所不同。

目的

在本研究中，我们试图调查PCSK9亚型是否与动脉粥样硬化性心血管事件相关。

方法

在一项日本队列流行病学研究——吹田研究中，我们调查了1436名未服用他汀类药物且无任何心血管疾病的日本受试者。通过酶联免疫吸附测定法测量总PCSK9、成熟PCSK9和经弗林蛋白酶切割的PCSK9水平。比较了按PCSK9水平三分位数分层的受试者中冠心病和中风事件的发生率。

结果

总PCSK9、成熟PCSK9和经弗林蛋白酶切割的PCSK9水平均与非高密度脂蛋白胆固醇相关（均P<0.001），并与收缩压相关（分别为P = 0.001、P = 0.004和P<0.001）。此外，只有经弗林蛋白酶切割的PCSK9水平与高敏C反应蛋白（hs-CRP）相关（P<0.001）。在13.6年的观察期内，经弗林蛋白酶切割的PCSK9水平预测发生冠心病事件的可能性更大（第二三分位数：风险比[HR]：2.84[95%置信区间[CI]：1.21 - 6.65；P = 0.01]；第三三分位数：HR：2.81[95% CI：1.17 - 6.74；P = 0.02]），但与中风无关（第二三分位数：HR：1.31[95% CI：0.72 - 2.40；P = 0.36]；第三三分位数：HR：1.27[95% CI：0.68 - 2.38；P = 0.44]）。总PCSK9和成熟PCSK9水平与冠心病事件无关（总PCSK9：第二三分位数：HR：1.35[95% CI：0.68 - 2.68；P = 0.39]；第三三分位数：HR：1.13[95% CI：0.54 - 2.34；P = 0.73]；成熟PCSK9：第二三分位数：HR：1.02[95% CI：0.52 - 2.02；P = 0.93]；第三三分位数：HR：0.96[95% CI：0.47 - 1.95；P = 0.92]），与中风事件也无关（总PCSK9：第二三分位数：HR：0.90[95% CI：0.50 - 1.61；P = 0.72]；第三三分位数：HR：0.99[95% CI：0.54 - 1.80；P = 0.97]；成熟PCSK9：第二三分位数：HR：0.86[95% CI：0.47 - 1.57；P = 0.63]；第三三分位数：HR：1.11[95% CI：0.61 - 1.99；P = 0.72]）。