Cardiovascular Biology and Biomechanics Laboratory, Cardiovascular Division, University of Nebraska Medical Center, 982265 Nebraska Medical Center, Omaha, NE, 68198, USA.
CGH Medical Center, Sterling, IL, and Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Curr Atheroscler Rep. 2018 Mar 10;20(4):20. doi: 10.1007/s11883-018-0718-x.
Clinical trials with PCSK9 inhibitors have shown a robust decrease in plasma LDL levels and a significant reduction in the incidence of cardiovascular atherosclerotic events. However, the role of PCSK9 in atherosclerosis is not well investigated and it remains unclear whether PCSK9 inhibition has direct, LDL-independent, anti-atherosclerotic effects. This review outlines the molecular pathways and targets of PCSK9 in atherosclerosis and summarizes the experimental and clinical data supporting the anti-atherosclerotic (pleiotropic) actions of PCSK9 inhibitors.
PCSK9 is expressed by various cell types that are involved in atherosclerosis (e.g., endothelial cell, smooth muscle cell, and macrophage) and is detected inside human atherosclerotic plaque. Preclinical studies have shown that inhibition of PCSK9 can attenuate atherogenesis and plaque inflammation. Besides increasing plasma LDL, PCSK9 appears to promote the initiation and progression of atherosclerosis. Inhibition of PCSK9 may confer atheroprotection that extends beyond its lipid-lowering effects.
PCSK9 抑制剂的临床试验表明，其能显著降低血浆 LDL 水平，并显著减少心血管动脉粥样硬化事件的发生。然而，PCSK9 在动脉粥样硬化中的作用尚未得到充分研究，目前尚不清楚 PCSK9 抑制是否具有直接的、非 LDL 依赖性的抗动脉粥样硬化作用。本文概述了 PCSK9 在动脉粥样硬化中的分子途径和靶点，并总结了支持 PCSK9 抑制剂抗动脉粥样硬化（多效性）作用的实验和临床数据。
PCSK9 由参与动脉粥样硬化的各种细胞（如内皮细胞、平滑肌细胞和巨噬细胞）表达，并在人动脉粥样硬化斑块中检测到。临床前研究表明，PCSK9 抑制可减轻动脉粥样硬化形成和斑块炎症。除了增加血浆 LDL 外，PCSK9 似乎还促进了动脉粥样硬化的发生和进展。PCSK9 抑制可能提供的动脉粥样硬化保护作用超出了其降低血脂的作用。
