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

Abstract

PurposeIncreased 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 MethodsStudies 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.ResultsThe 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).ConclusionDarapladib, a Lp-PLA2 inhibitor, leads to cardiovascular protection that might be mediated by its inhibition of both Rho kinase and Lp-PLA2 in atherosclerosis.

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

“…5) is a potent and selective inhibitor of LpPLA 2 (IC 50 0.25 nM against recombinant human LpPLA 2 in a DNPG assay), developed by GlaxoSmithKline [111], that has undergone two phase 3 trials for cardiovascular disease, but has been discontinued because of failure to reduce the risk of major coronary events [112,113]. Recently, darapladib was found to reduce elevated LpPLA 2 , Rho kinase activity, and cardiomyocyte apoptosis in atherosclerosis, which can lead to cardiovascular protection [114]. In an in vivo rat type 2 diabetes mellitus model, darapladib was proven to reduce inflammation [115], to decrease vascular cell adhesion molecule-1 and intercellular adhesion molecules-1 aorta expression in early stages of atherosclerosis [116] and to improve insulin resistance occurring in the metabolic disorder [117].…”

Roles of Reconstituted High-Density Lipoprotein Nanoparticles in Cardiovascular Disease: A New Paradigm for Drug Discovery

“…Emerging therapeutic approaches targeting rHDL have been investigated to reduce the risk of cardiovascular events in the past decades [52,53]. One of the important therapies is apoAI Milano (apoA-IM), a naturally occurring mutant of apoAI that was shown to be related with cardioprotective effects [54].…”

Inhibition of�Rho‑kinase is involved in the therapeutic effects of atorvastatin in heart ischemia/reperfusion

“…The ubiquitously expressed Rho-kinase, which is a serine/threonine kinase, has been reported to serve an important role in a number of major cardiovascular diseases, such as hypertension, heart failure, pulmonary hypertension, atherosclerosis, myocardial infarction and myocardial I/R (5)(6)(7)(8)(9)(10)(11). Previous studies have demonstrated that Rho-kinase activation is involved in the pathogenesis of I/R in vivo (12)(13)(14)(15)(16).…”