Zhang Juan, Xu Dong Ling, Liu Xiao Bo, Bi Shao Jie, Zhao Tong, Sui Shu Jian, Ji Xiao Ping, Lu Qing Hua
Department of Cardiology, The Second Hospital of Shandong University, Jinan, Shandong Province, China.
Shandong Blood Center, Jinan, Shandong Province, China.
Yonsei Med J. 2016 Mar;57(2):321-7. doi: 10.3349/ymj.2016.57.2.321.
Increased lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and Rho kinase activity may be associated with atherosclerosis. The principal aim of this study was to examine whether darapladib (a selective Lp-PLA2 inhibitor) could reduce the elevated Lp-PLA2 and Rho kinase activity in atherosclerosis.
Studies were performed in male Sprague-Dawley rats. The atherosclerosis rats were prepared by feeding them with a high-cholesterol diet for 10 weeks. Low-dose darapladib (25 mg·kg⁻¹·d⁻¹) and high-dose darapladib (50 mg·kg⁻¹·d⁻¹) interventions were then administered over the course of 2 weeks.
The serum levels of triglycerides, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), high-sensitivity C-reactive protein (hs-CRP), and Lp-PLA2, significantly increased in atherosclerosis model groups, as did Rho kinase activity and cardiomyocyte apoptosis (p<0.05 vs. sham group), whereas nitric oxide (NO) production was reduced. Levels of TC, LDL-C, CRP, Lp-PLA2, and Rho kinase activity were respectively reduced in darapladib groups, whereas NO production was enhanced. When compared to the low-dose darapladib group, the reduction of the levels of TC, LDL-C, CRP, and Lp-PLA2 was more prominent in the high-dose darapladib group (p<0.05), and the increase of NO production was more prominent (p<0.05). Cardiomyocyte apoptosis of the high-dose darapladib group was also significantly reduced compared to the low-dose darapladib group (p<0.05). However, there was no significant difference in Rho kinase activity between the low-dose darapladib group and the high-dose darapladib group (p>0.05).
Darapladib, a Lp-PLA2 inhibitor, leads to cardiovascular protection that might be mediated by its inhibition of both Rho kinase and Lp-PLA2 in atherosclerosis.
脂蛋白相关磷脂酶A2（Lp-PLA2）活性和Rho激酶活性升高可能与动脉粥样硬化有关。本研究的主要目的是检验达帕利单抗（一种选择性Lp-PLA2抑制剂）是否能降低动脉粥样硬化中升高的Lp-PLA2和Rho激酶活性。
在雄性Sprague-Dawley大鼠中进行研究。通过给大鼠喂食高胆固醇饮食10周制备动脉粥样硬化大鼠。然后在2周的时间内给予低剂量达帕利单抗（25 mg·kg⁻¹·d⁻¹）和高剂量达帕利单抗（50 mg·kg⁻¹·d⁻¹）干预。
动脉粥样硬化模型组的甘油三酯、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）、高敏C反应蛋白（hs-CRP）和Lp-PLA2的血清水平显著升高，Rho激酶活性和心肌细胞凋亡也显著升高（与假手术组相比，p<0.05），而一氧化氮（NO）生成减少。达帕利单抗组的TC、LDL-C、CRP、Lp-PLA2水平和Rho激酶活性分别降低，而NO生成增加。与低剂量达帕利单抗组相比，高剂量达帕利单抗组的TC、LDL-C、CRP和Lp-PLA2水平降低更显著（p<0.05），NO生成增加更显著（p<0.05）。高剂量达帕利单抗组的心肌细胞凋亡也比低剂量达帕利单抗组显著减少（p<0.05）。然而，低剂量达帕利单抗组和高剂量达帕利单抗组之间的Rho激酶活性没有显著差异（p>0.05）。
Lp-PLA2抑制剂达帕利单抗可通过抑制动脉粥样硬化中的Rho激酶和Lp-PLA2介导心血管保护作用。
