Dissertation
Dissertation > Medicine, health > Internal Medicine > Heart, blood vessels ( circulatory ) disease > Vascular disease

Influence of Estradiol on Macrophage Phagocytosis Function and Its Mechanism Study

Author LiuYuYan
Tutor XiangJiZhou
School Huazhong University of Science and Technology
Course Pharmacology
Keywords Estradiol Macrophages Oxidized low-density lipoprotein Inducible nitric oxide synthase Nitric oxide Scavenger receptor CD36 SR-BI Arginase Ⅰ
CLC R543
Type Master's thesis
Year 2009
Downloads 76
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Research background and purpose of atherosclerosis is a dyslipidemia and vascular wall composition changes related artery disease. Lipids in the arterial intima the deposition [1] , caused by fibrous intimal thickening ingredients deep necrosis, collapse to form a porridge-like material. Adult women increases with age, estrogen levels gradually decreased [2] overall incidence rate than premenopausal women atherosclerotic heart disease in postmenopausal women [3 low the . The traditional view has long been that: estrogen from the protective effect of atherosclerosis, which is also whole animal experiments the support [4] , and its protective mechanisms include lipid metabolic pathways (such as lower LDL, increased HDL) and non-lipid metabolic pathways (such as stable atherosclerotic plaque) the [4-5] . However, clinical studies have found that postmenopausal women estrogen replacement therapy was able to increase myocardial infarction, stroke, venous thrombosis, breast cancer, endometrial cancer risk [6] . Further study showed that: early premenopausal, menopausal or post-menopausal estrogen replacement therapy help to reduce the incidence of atherosclerotic disease risk, but postmenopausal women with advanced estrogen replacement therapy, but so that the increased risk of atherosclerosis disease [7] , the two-way role of estrogen in different ages showed no good explanation. Initiating factor of atherosclerosis is due to macrophages swallowed modified low-density lipoprotein accumulation of plaque in the aorta wall. Various risk factors can damage endothelial cells, monocytes by cell adhesion molecule (VCAM, ICAM, selectins, etc.) and adhesion to endothelial cells and endothelial migration. Including subcutaneous, monocyte macrophage colony stimulating factor (MCSF) differentiation into macrophage phagocytosis of the oxidation of low density lipoprotein (ox-LDL via the scavenger receptor (SR-A and CD36, etc.) ) gradual formation of foam cells, macrophages play a crucial role in the start and development of atherosclerosis [1] . Occurrence and development of atherosclerosis can actually be seen as macrophage reaction of endogenous foreign body (ox-LDL) Clear monocyte adhesion, migration, differentiation, phagocytosis and the formation of foam cells is the the process key [1] : large amounts of NO, generated by the monocyte / macrophage iNOS oxidative stress can lead to the oxidation of LDL to Ox-LDL or nitro LDL (NO < sub> 2 -LDL), Ox-LDL through MAPK phosphorylation in regulating the activity of PPARγ, the increase of CD36 expression, thereby promoting macrophage phagocytosis of Ox-LDL, promote the formation of foam cells [1] ;, Ox-LDL can also be a direct result of phosphorylation of JNK, thereby promoting another scavenger receptor SR-A the phosphorylation [1] , and expression increased , thereby promoting macrophage phagocytosis of Ox-LDL, promote the formation of foam cells; [1] of iNOS can also be induced macrophage apoptosis addition, NO through different mechanisms regulating IL-8 and TNF- a generation of macrophages in the induction of TNF-α, IL -1 of macrophages can release metalloproteinase (MMP) the protein [8] metalloproteinase can specifically bind to the extracellular matrix (ECM) components combined and degradation weakened neovascularization increased formation of plaque instability, and promote plaque rupture and thrombosis [1] . Visible, monocyte / macrophages in atherosclerotic occurrence and development of the inflammatory response plays a very important role, its targets has become very important new treatment of atherosclerosis research showed that in the human Therefore, postmenopausal women with advanced estrogen replacement therapy for women, due to the pro-inflammatory effect of estrogen, resulting in atherosclerotic plaque instability induced acute vascular events, eventually leading to increased risk of atherosclerotic disease. However, a single dose-effect relationship \To explain this paradox, this study intends to target cells through the establishment of Ox-LDL-induced macrophage cell-derived foam cells induced murine monocyte-derived macrophages RAW264 given different doses of estradiol intervention observation estradiol (E , 2 ) Ox-LDL-induced macrophage phagocytosis, and to study its possible mechanism. Method murine monocyte-derived macrophages RAW264 7 cell culture, into without Ox-LDL induced group and by 75 mg · L -1 ox-LDL-induced induction of 12-hour group . Ox-LDL-induced group was divided into blank control group, DMSO group (solvent control), l pmol · L -1 E 2 group, 25 pmol · L -1 E 2 group, 50 pmol · L -1 E 2 group, 100 pmol · L - 1 E 2 group oil red staining macrophage phagocytosis of Ox-LDL, semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) determination of macrophage scavenger receptor CD36, SR-BI arginine enzyme I (ARG1), the expression of inducible nitric oxide synthase (iNOS) mRNA, Nitroreductase method for the determination of the content of NO results without Ox-LDL induced group compared macrophages induced by Ox-LDL blank control group significantly increased the phagocytosis of lipid droplets, CD36, SR-BI, iNOS, ARG1 mRNA expression was significantly increased the content of NO in the cell culture medium was significantly increased (P lt; 0.05); induced by ox-LDL DMSO group, l pmol · L -1 E 2 group and the control group, macrophage phagocytosis of lipid droplets, CD36 SR-BI mRNA expression of iNOS, ARG1, the content of NO in the cell culture medium was no significant difference, however, in the ox-LDL induced group 25 pmol · L -1 , 50 pmol · L -1 , 100 pmol · L -1 E 2 group macrophage phagocytosis of lipid droplets than the ox- LDL-induced DMSO group were significantly increased, CD36mRNA expression significantly increased iNOS mRNA expression was significantly sexual increase ARG1 mRNA expression was significantly sexually reduce, the content of the cell culture fluid NO the significant increase (P lt; 0.05), and was against the concentration trends. Expression of SR-BI mRNA of no significant difference. E 2 (1 ~ 100 pmol / L) can promote phagocytosis of mouse-derived monocyte-macrophage cells RAW264 7 of Ox-LDL, promote the expression of CD36 mRNA and to promote iNOS mRNA expression and NO generation, the role of showing \Conclusion E 2 (1 to 100 pmol L -1 ) can promote phagocytosis of mouse-derived monocyte-macrophage cells RAW264 Ox-LDL, promote CD36 mRNA expression may Since E 2 proinflammatory effect. E 2 to promote the tendency to increased risk of atherosclerotic disease, the role of showing the parabolic trend, and its mechanism to promote macrophage iNOS expression of proinflammatory cytokines to promote the formation of NO, a large number of NO caused by oxidative stress, oxidized LDL and promote CD36 mRNA expression, macrophage Ox-LDL gradually formed foam cells, leading to the occurrence of atherosclerosis.

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