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Mechanism of Oxidized Low-Density Lipoprotein Activating ERK and PI3K/AKT Signal Pathway

Author: LinZongWei
Tutor: JiangYiNong
School: Dalian Medical University
Course: Internal Medicine
Keywords: HUVECs ox-LDL ERK1/2 PI3K/AKT angiotensinⅡ
CLC: R543.5
Type: Master's thesis
Year: 2011
Downloads: 74
Quote: 1
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Abstract


Background:Atherosclerosis （AS） is the main disease that seriously affects the health of human being. The research of its mechanism has been going on for decades.Now most scholars support atheroslerosis response to injury,which says the injury of endothelial cells is the initiating agent in AS,while the atheromatous plaque formation is the result of injury response to endarterium. Many risk factors which cause AS can activate some signal pathway and inflammatory factors to cause endothelial dysfunction, including oxidative modificated LDL and hypertension.Oxidized low- density liporoteins （ox-LDL） exert various biological effects potentially involved in atherosclerosis development, such as chemotaxis, cell proliferation or cytotoxicity. In contrast, hypertension is mainly embodied in the influence of renin-angiotensin system （RAS）, and angiotensinⅡ（AngⅡ）is main actived substance for the systerm. In recent years,it has been found that RAS has other new important members: angiotensin converting enzyme （ACE） 2, Ang - （1-7）, Ang - （1-7） receptor Mas, （pro） renin receptor [（P）RR] and so on. Very recently, our task group has been the pioneer in finding （pro）renin receptor （P）RR expression in human umbilical vein endothelial cell （HUVEC） by immunohistochemistry. The combination of （pro）renin and （P）RR can activate the intracellular signalling pathways, and up-regulate some gene expression through the independent AngⅡ.Some studies have shown, ox-LDL and AngⅡhave synergistic action to promote atherosclerosis. Angiotensin 1-converting enzyme gene expression induced by ox-LDL,increasing more AngⅡcombine with ox-LDL. However, it is not clear whether the intracellular signalling pathways activation and some gene expression are dependent on AngⅡway or other RAS ways such as （P）RR system and Ang-（1-7） induced by ox-LDL.Objectives:To observe the PI3K/AKT and ERK1/2 activation induced by ox-LDL. Thus,to study whether PI3K/AKT and ERK1/2 signaling pathways can be activated by ox-LDL in HUVECs through the AngⅡway,discuss the mechanism of atherosclerosis induced by ox-LDL.Methods:1. HUVECs were cultured in vitro.2.ox-LDL stimulated HUVECs with differernt time and concentration,to observe the influence of the ERK and PI3K/AKT pathways .3. AT1/AT2 receptors of AngⅡwere blocked by olmesartan(10-5M) and PD123319(10-4M) respectively to observe the ox-LDL’s effect on the expression of ERK,PERK,AKT and PAKT in HUVECs.4. PI3K/AKT signal transduction pathway was blocked with wortm - annin(0.5×10-6M), the changes of PAKT were observed.5.ERK signal transduction pathway was blocked with PD98059, the changes of ERK and PERK were observed.6.ERK,PERK,AKT and PAKT were evaluated by western blot.Results:1. The protein expression of ERK and AKT did not modify significantly with ox-LDL in different times, while the expression of PERK and PAKT was time dependent,and largest in 15min;the expression of PERK was largest at 100ug/ml ox-LDL.2. ERK protein expression did not modify,but the phosphorylated ERK protein expression down-regulated under the condition of blocking AT1 and AT2 and ERK pathway .3. The phosphorylated AKT protein expression down-regulated under the condition of blocking AT1 and AT2 and PI3K/AKT pathway .Conclusions:1.ox-LDL up-regulate the phosphorylated ERK and AKT protein expression ,but have no influence on ERK and AKT.2. The phosphorylated ERK and AKT protein expression are induced by ox-LDL in a time and concentration-dependent manner.3. The phosphorylated ERK and AKT protein expression are not activated by ox-LDL through angiotensinⅡ, suggested that they may be activated through other pathways, and could be blocked by PD98059 and wortmannin.

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CLC: > Medicine, health > Internal Medicine > Heart, blood vessels ( circulatory ) disease > Vascular disease > Artery disease
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