Elaborate evaluation of serum and tissue oxidized LDL level with darapladib therapy:A feasible diagnostic marker for early atherogenesis

Objective: To compare oxidized low density lipoprotein (oxLDL) levels in serum and vascular wall of Sprague-Dawley rats, identify their patterns in 8 weeks and 16 weeks of dyslipidemia induced by high fat diet, compare foam cells in aorta of each group and investigate lipoprotein-associated phospholipase A2 (Lp-PLA2) role in atherosclerosis by darapladib administration. Methods: This study generated in twenty-four Sprague-Dawley rats. Rats were divided into 6 groups, which were received normal diet (normal group), high fat diet and high fat diet plus darapladib therapy for both 8 weeks and 16 weeks. Surgeries were performed at Week 8 and Week 16 to take the blood serum and aortic tissue. Level of oxLDL in serum, oxLDL aortic tissue, foam cell amount in aortic tissue, and Lp-PLA2 expression in aortic tissue were measured. Results: There were significant differences in oxLDL level in serum, aortic tissue and foam cell amount (P0.9, P<0.05). This study also composed an equation for oxLDL level in aortic tissue prediction. Factorial ANOVA found that there was a significant difference of oxLDL level in the interactions between duration and location, location and treatment, and also duration, location and treat-ment (P<0.01). Administration of darapladib was able to reduce levels of oxLDL in serum, aortic tissue and foam cell significantly (P<0.05, P<0.05 and P<0.01, subsequently). Conclusions: OxLDL level is location-dependent and duration-dependent. As a feasible early diagnosis, we can predict oxLDL level in aortic tissue by its level in serum. Though Lp-PLA2 expression was unsignificant, Lp-PLA2 inhibition by darapladib can reduce oxidative stress and inflammation in atherogenesis.

Elaborate evaluation of serum and tissue oxidized LDL level with darapladib therapy: A feasible diagnostic marker for early atherogenesis

Objective To compare oxidized low density lipoprotein (oxLDL) levels in serum and vascular wall of Sprague-Dawley rats, identify their patterns in 8 weeks and 16 weeks of dyslipidemia induced by high fat diet, compare foam cells in aorta of each group and investigate lipoprotein-associated phospholipase A

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

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 (p0.05). 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.

Lipoprotein-associated phospholipase A2 and coronary heart disease / 中华检验医学杂志

Lp-PLA2 is widely concerned in recent years as a vascular inflammation factor that plays an important role in the development of atherosclerosis .The level of plasma Lp-PLA2 is related to the stability of carotid artery atherosclerotic plaque .it is an independent predictor of coronary heart disease risk . Its specific inhibitor Darapladib also becomes a hotspot of clinical cardiovascular pharmaceutical research . However,two randomized, placebo-controlled, double-blind, international, multicenter, event-driven trials, STABILITY and SOLID-TIMI 52, have shown that Darapladib could not significantly reduce the risk of cardiovascular events.

Pharmacodynamics recent advances of a lipoprotein-associated phospholipase A2 specific inhibitor darapladib / 中国药学杂志

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a member of phospholipases superfamily which can hydrolyze oxidative phospholipid in low density lipoprotein (LDL), and produce two proinflammatory mediators including lysophosphatidylcholine (IvsoPC) and oxidized free fatty acid. Thus, Lp-PLA2 is believed to mediate the inflammatory processes that lead to atherogenesis. Recent studies indicated that Lp-PLA2 acts as a new marker in the inflammatory process and is an independent predictor of the cardiovascular diseases. Many Lp-PLA2-targeted inhibitors have been designed to deal with the key enzyme involving in atherosclerosis. Darapladib is the specific inhibitor which is closest to the market among the rest and is drawn wide attention as an emerging therapy for atherosclerosis, and the clinical phase III trials have been completed. Numerous experiments have confirmed that Darapladib could decrease the activity of Lp-PLA2, reduce inflammatory reaction and disrupt the development of atherosclerosis. In this paper, the authors summarized the mechanism of Lp-PLA2 and Darapladib in atherosclerosis, and the recent advances on the pharmacodynamics of Darapladib in recent years.