Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, Reduces Rho Kinase Activity in Atherosclerosis.
10.3349/ymj.2016.57.2.321
- Author:
Juan ZHANG
1
;
Dong Ling XU
;
Xiao Bo LIU
;
Shao Jie BI
;
Tong ZHAO
;
Shu Jian SUI
;
Xiao Ping JI
;
Qing Hua LU
Author Information
1. Department of Cardiology, The Second Hospital of Shandong University, Jinan, Shandong Province, China. awwa6940@sina.com
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
Atherosclerosis;
lipoprotein-associated phospholipase A2 darapladib;
Rho kinase;
apoptosis
- MeSH:
1-Alkyl-2-acetylglycerophosphocholine Esterase/*antagonists & inhibitors/blood/drug effects;
Animals;
Atherosclerosis/blood/*drug therapy/*enzymology;
*Benzaldehydes;
C-Reactive Protein/metabolism;
Cholesterol/blood;
Cholesterol, HDL/blood;
Cholesterol, LDL/blood;
Dose-Response Relationship, Drug;
Male;
*Oximes;
Phospholipase A2 Inhibitors/*administration & dosage/adverse effects;
Rats;
Rats, Sprague-Dawley;
Triglycerides/blood;
rho-Associated Kinases/*metabolism
- From:Yonsei Medical Journal
2016;57(2):321-327
- CountryRepublic of Korea
- Language:English
-
Abstract:
PURPOSE: 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. MATERIALS AND 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). CONCLUSION: 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.
