Yonsei Med J.  2016 Mar;57(2):321-327. 10.3349/ymj.2016.57.2.321.

Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, Reduces Rho Kinase Activity in Atherosclerosis

• Zhang J
• Xu DL
• Liu XB
• Bi SJ
• Zhao T
• Sui SJ
• Ji XP
• Lu QH

• KMID: 2374035
• DOI: http://doi.org/10.3349/ymj.2016.57.2.321

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.

Keyword

Atherosclerosis; lipoprotein-associated phospholipase A2 darapladib; Rho kinase; apoptosis

MeSH Terms

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
1-Alkyl-2-acetylglycerophosphocholine Esterase
Benzaldehydes
C-Reactive Protein
Cholesterol
Cholesterol, HDL
Cholesterol, LDL
Oximes
Phospholipase A2 Inhibitors
Triglycerides
rho-Associated Kinases

Figure

• 

  Fig. 1 Representative photomicrographs of ventricular tissue stained via TUNEL for DNA breaks. (A) Sham group. (B) Control atherosclerosis (AS) group. (C) AS+low-dose darapladib group. (D) AS+high-dose darapladib group. In the atherosclerosis group an increased number of TUNEL-positive cells was observed (*p<0.05 vs. sham group). After administration of darapladib, the percentage of TUNEL-positive cells was significantly reduced (†p<0.05 vs. control AS group). The percentage of TUNEL-positive cells of the high-dose darapladib group was significantly lower than the low-dose darapladib group (‡p<0.05). Black arrows show the TUNEL-positive cells. TUNEL, transferase-mediated dUTP nick end labeling.

• 

  Fig. 2 Western blot analysis of MYPT-1 phosphorylation in rat hearts of different groups (sham, AS, AS+low-dose darapladib, AS+high-dose darapladib). After administration of darapladib, the phosphorylation of p-MYPT-1 was significantly attenuated (†p<0.05 vs. control AS group). There was no significant difference between the low-dose darapladib group and the high-dose darapladib group (p>0.05). *p<0.05 vs. sham group. MYPT-1, myosin phosphatase targeting subunit 1; AS, atherosclerosis.

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