Lowering Inflammation Level by Lp-PLA2 Inhibitor (Darapladib) in Early Atherosclerosis Development: in vivo Rat Type 2 Diabetes Mellitus Model

Abstract

Background: Type 2 Diabetes Melitus (T2DM) is a condition of insulin resistance that causes extensive tissue damage due to vascular inflammation and oxidative stress. Lipoprotein-associated phospholipase A2 (Lp-PLA2) has anti-inflammatory role as it hydrolyzes atherogenesis mediators such as oxidized LDL (Ox LDL) and platelet activating factor (PAF) but in contrast, it has pro inflammatory effect as it produced lysophosphatidylcholine (lysoPC) and oxidized fatty acid (oxFA). Methods and Results: This study aimed to measure inflammation marker of T2DM in vivo model with Lp-PLA2 selective inhibitor (darapladib) treatment. It used true experimental laboratory and post test only with control group design using 30 spraque dowley rats that is divided into 3 main groups: normal, T2DM, and T2DM with darapladib (DMDP) administration group. Each group are divided into 2 serial treatment times: 8-weeks and 16-weeks intervention. So, there are 6 groups total with 5 rat in each group. Parameter measured was ox-LDL, tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), interleukin 6 (IL-6), PAF, perivascular adipose tissue (PAT) thickness and also blood glucose, lipid profile, and insulin plasma level. ANOVA test result showed that darapladib were significantly (p: 0.000) lowering tissue and blood ox-LDL level, iNOS, PAF, IL-6 and PAT thickness on T2DM in vivo model. Conclusions: Darapladib proved to have anti inflammation role on T2DM model.

<p>Lp-PLA₂ Selective Inhibitor (Darapladib) Effect In Lowering The Expression Level Of IL-1B And IL-6 In The Renal At Type 2 Diabetes Mellitus</p>

“…The result can be seen in our previous publication by Heriansyah (2017). T2DM model was made successfully if fasting blood glucose >126 mg/dl and insulin resistance (using HOMA-IR) results >1.716 11. 20 mg/kg BW/day of darapladib given to T2DM group showed a decreasing in LDL and total cholesterol and an increase in HDL both in 8 weeks and 16 weeks.…”

“…The state of Hyperglycemia can increase NADPH oxidase complex which results in increased production of reactive oxygen species (ROS) and triggers Ox-LDL resulting in increased oxidative stress and release NF-κB from the cytoplasm to the nucleus that causes the transactivation of multiple pro-inflammatory agents 23–25. Lyso PC and ox NEFA produced by Lp-PLA2 action through ox-LDL are able to promote monocyte migration by inducing monocyte chemotactic protein (MCP)-1 and stimulating Interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α production and scavenger receptor expression in macrophages in a concentration-dependent manner 11. Hyperglycemia also increases the NF-κB level, resulting in increased levels of CAMs.…”

“…IL-1B is known as an inflammatory marker that has an important role in the pathogenesis of atherosclerosis 10. Expression and secretion of IL-6 are regulated by IL-1 and TNF-a, which are highly induced in the atherosclerotic plaque 11…”