title: Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, Reduces Rho Kinase Activity in Atherosclerosis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors: Department of Cardiology, The Second Hospital of Shandong University, Jinan, Shandong Province, China. awwa6940@sina.com.
authors: Juan
authors: J
authors: Zhang
authors: Department of Cardiology, The Second Hospital of Shandong University, Jinan, Shandong Province, China.
authors: Dong Ling
authors: DL
authors: Xu
authors: Shandong Blood Center, Jinan, Shandong Province, China.
authors: Xiao Bo
authors: XB
authors: Liu
authors: Department of Cardiology, The Second Hospital of Shandong University, Jinan, Shandong Province, China.
authors: Shao Jie
authors: SJ
authors: Bi
authors: Department of Cardiology, The Second Hospital of Shandong University, Jinan, Shandong Province, China.
authors: Tong
authors: T
authors: Zhao
authors: Department of Cardiology, The Second Hospital of Shandong University, Jinan, Shandong Province, China.
authors: Shu Jian
authors: SJ
authors: Sui
authors: The Key Laboratory of Cardiovascular Remodeling and Function Research of the Chinese Ministry of Education and Public Health, Shandong University Qilu Hospital, Jinan, Shandong Province, China.
authors: Xiao Ping
authors: XP
authors: Ji
authors: Department of Cardiology, The Second Hospital of Shandong University, Jinan, Shandong Province, China. lqhzhy@163.com.
authors: Qing Hua
authors: QH
authors: Lu
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000187:drug effects; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology*; D001547:Benzaldehydes; D002097:C-Reactive Protein / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D008297:Male; D010091:Oximes; D064801:Phospholipase A2 Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood; D054460:rho-Associated Kinases / Q000378:metabolism*; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes; D002097:C-Reactive Protein; D002784:Cholesterol; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D010091:Oximes; D064801:Phospholipase A2 Inhibitors; D014280:Triglycerides; D054460:rho-Associated Kinases; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
keywords: Atherosclerosis; Rho kinase; apoptosis; lipoprotein-associated phospholipase A2 darapladib