Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal (IRCM), 110 Pine Avenue West, Montreal, QC, H2W 1R7, Canada.
Curr Atheroscler Rep. 2010 Sep;12(5):308-15. doi: 10.1007/s11883-010-0123-6.
Pro-protein-convertase-subtilisin-kexin-9 (PCSK9) enhances the degradation of the low-density lipoprotein receptor (LDLR) that plays a major role in cholesterol homeostasis. Recent advances have revealed a large number of genetic variants of PCSK9 that may modulate plasma cholesterol levels either positively or negatively, therefore influencing the risk of atherosclerosis. Recognition of these mutants may have clinical implication in assessing severity of disease, prognosis, or response to drug therapy. PCSK9's expression, secretion, and plasma levels maybe modulated by the proprotein convertase furin, by natural inhibitors (annexin-A2), or influenced by lipid-altering agents such as statins, fibrates, ezetimibe, and berberine. It is now a prime target for therapy, prompting the development of various approaches to reduce its LDLR degrading activity, including antibody neutralization, anti-sense oligonucleotides such as phosphorothioates, locked nucleic acids, and RNA interference, and eventually small molecule inhibitors. Which one will be clinically applicable will depend on long-term effects, cost, and ease of administration.
前蛋白转化酶枯草溶菌素 9（PCSK9）可增强在胆固醇稳态中起主要作用的低密度脂蛋白受体（LDLR）的降解。最近的研究揭示了大量的 PCSK9 遗传变异，这些变异可能通过正或负方式调节血浆胆固醇水平，从而影响动脉粥样硬化的风险。识别这些突变体可能对评估疾病严重程度、预后或药物治疗反应具有临床意义。PCSK9 的表达、分泌和血浆水平可能受到前蛋白转化酶枯草溶菌素、天然抑制剂（膜联蛋白 A2）的调节，也可能受到调脂药物如他汀类药物、贝特类药物、依折麦布和小檗碱的影响。目前，它是治疗的主要靶点，促使人们开发了各种方法来降低其 LDLR 降解活性，包括抗体中和、反义寡核苷酸如硫代磷酸酯、锁核酸和 RNA 干扰，最终是小分子抑制剂。哪一种方法在临床上适用将取决于长期效果、成本和给药的便利性。
