Koppe Cordelia, Rodríguez Miguel, Winkler Karl, Pietzsch Jens, Neumann Konrad, Hiemann Nicola E, Hetzer Roland, Malmsten Martin, Siegel Günter
Institute of Physiology, Charité, Campus Benjamin Franklin, Berlin, Germany.
Forsch Komplementmed. 2009 Aug;16(4):237-45. doi: 10.1159/000229786. Epub 2009 Aug 13.
BACKGROUND/METHODS: Coating a silica surface with the isolated lipoprotein receptor heparan sulfate proteoglycan (HS-PG) from arterial endothelium and vascular matrices, we could observe the very earliest stages of arteriosclerotic plaque development by ellipsometric techniques in vitro (patent EP 0 946 876). This so-called nanoplaque formation is represented by the ternary aggregational complex of the HS-PG receptor, lipoprotein particles and calcium ions. The model was validated in several clinical studies on statins in cardiovascular high-risk patients applying their native blood lipoprotein fractions.
In 7 patients who had undergone a valvular defect operation, the reduction of arteriosclerotic nanoplaque formation in normal Krebs solution amounted to 6.1 +/- 2.3% (p < 0.0156) and of nanoplaque size to 37.5 +/- 13.2% (p < 0.0312), respectively, after a 3-month therapy with n-3 fatty acids (3 ..3 g daily, Ameu 500 mg). Additionally, the quotient oxLDL/LDL was lowered by 6.8 +/- 2.1% (p < 0.0166), the MDA concentration remained unchanged and the lipoprotein(a) concentration decreased by 15.8 +/- 5.6% (p < 0.0469) in the patients' blood. The concentration of the nanoplaque promoting particles VLDL and total triglycerides was diminished by 34.1 +/- 11.6% (p < 0.0469) and 26.7 +/- 10.8% (p < 0.0156), respectively. Furthermore, the ratio of the strongly atherogenic small dense to the total LDL cholesterol (LDL5+LDL6)/LDLtot decreased by 9.9 +/- 3.0% (p < 0.0174).
A combinatorial regression analysis revealed a basis for a mechanistic explanation of nanoplaque reduction under n-3 fatty acid treatment. This effect was possibly due to the beneficial changes in lipid concentrations and an attenuation of the risk factors oxLDL/LDL and (LDL5+LDL6)/LDLtot.
背景/方法：通过用从动脉内皮和血管基质中分离出的脂蛋白受体硫酸乙酰肝素蛋白聚糖（HS-PG）包被二氧化硅表面，我们能够在体外通过椭圆偏振技术观察动脉粥样硬化斑块形成的最初阶段（专利EP 0 946 876）。这种所谓的纳米斑块形成由HS-PG受体、脂蛋白颗粒和钙离子的三元聚集复合物表示。该模型在多项关于他汀类药物用于心血管高危患者的临床研究中得到验证，这些研究使用了患者的天然血液脂蛋白组分。
在7例接受瓣膜缺损手术的患者中，经过3个月的n-3脂肪酸（每日3.3 g，Ameu 500 mg）治疗后，正常 Krebs 溶液中动脉粥样硬化纳米斑块形成的减少量分别为6.1±2.3%（p<0.0156），纳米斑块大小的减少量为37.5±13.2%（p<0.0312）。此外，患者血液中氧化低密度脂蛋白/低密度脂蛋白（oxLDL/LDL）的比值降低了6.8±2.1%（p<0.0166），丙二醛（MDA）浓度保持不变，脂蛋白（a）浓度降低了15.8±5.6%（p<0.0469）。促进纳米斑块形成的颗粒极低密度脂蛋白（VLDL）和总甘油三酯的浓度分别降低了34.1±11.6%（p<0.0469）和26.7±10.8%（p<0.0156）。此外，具有强烈致动脉粥样硬化作用的小而密低密度脂蛋白与总低密度脂蛋白胆固醇的比值（LDL5+LDL6）/LDLtot降低了9.9±3.0%（p<0.0174）。
组合回归分析揭示了n-3脂肪酸治疗下纳米斑块减少的机制解释基础。这种效果可能归因于脂质浓度的有益变化以及氧化低密度脂蛋白/低密度脂蛋白（oxLDL/LDL）和（LDL5+LDL6）/LDLtot等危险因素的减弱。
