Madasamy Shanmugavel, Shivasubramani Umadevi, Villanueva Jasmine, Bigos Marty, Amento Edward P, Wu Alan H B
Plaxgen Inc., Fremont, California.
Plaxgen Inc., Fremont, California.
Am J Cardiol. 2016 Oct 15;118(8):1187-1193. doi: 10.1016/j.amjcard.2016.07.035. Epub 2016 Jul 29.
Statin drugs are leading medication prescribed for treatment of dyslipidemic patients aimed at preventing both primary and secondary incidences of atherosclerosis-related cardiovascular events. Statin drugs competitively inhibit HMG-CoA reductase enzyme activity, thereby inhibiting cell-mediated cholesterol synthesis and reducing the low-density lipoprotein (LDL) cholesterol concentration of plasma. Conversely, the mechanism by which statins increase high-density lipoprotein (HDL) cholesterol concentration of plasma is not well understood. The plaque array method was used to examine the effect of statins on in vitro cholesterol particle formation. We observed that statins induced high-density cholesterol particle formation in buffer solution with or without the addition of human serum. Besides, simvastatin and lovastatin in their inactive pro-drug forms modulate formation of LDL and HDL cholesterol particles, indicating a novel nonenzymatic mechanism of statins. In a pilot study, screening of serum samples in the assay showed variation among patient samples in response to different statins. Specifically, screening of 50 serum samples with high cholesterol and statin treatment, compared with standard LDL-based measurement of statin efficacy, showed a good correlation for simvastatin (88%) and atorvastatin (84%). Taken together, our data indicate that statins, in addition to inhibiting enzyme-mediated cholesterol synthesis, have the capability to nonenzymatically modulate formation of LDL and HDL cholesterol particles in vitro. Similar interactions occurring in serum may provide a means to alter cholesterol particle formation in vivo.
他汀类药物是治疗血脂异常患者的主要处方药，旨在预防动脉粥样硬化相关心血管事件的一级和二级发病率。他汀类药物竞争性抑制HMG-CoA还原酶的活性，从而抑制细胞介导的胆固醇合成并降低血浆中低密度脂蛋白（LDL）胆固醇的浓度。相反，他汀类药物增加血浆中高密度脂蛋白（HDL）胆固醇浓度的机制尚不清楚。采用菌斑阵列法研究他汀类药物对体外胆固醇颗粒形成的影响。我们观察到，无论是否添加人血清，他汀类药物均可在缓冲溶液中诱导高密度胆固醇颗粒的形成。此外，辛伐他汀和洛伐他汀的无活性前药形式可调节LDL和HDL胆固醇颗粒的形成，这表明他汀类药物存在一种新的非酶促机制。在一项初步研究中，检测血清样本时发现患者样本对不同他汀类药物的反应存在差异。具体而言，对50份高胆固醇血清样本进行他汀类药物治疗，并与基于标准LDL的他汀类药物疗效测量方法进行比较，结果显示辛伐他汀（88%）和阿托伐他汀（84%）的相关性良好。综上所述，我们的数据表明，他汀类药物除了抑制酶介导的胆固醇合成外，还能够在体外非酶促调节LDL和HDL胆固醇颗粒的形成。血清中发生的类似相互作用可能为改变体内胆固醇颗粒的形成提供一种手段。
