Mechanism of anti-atherosclerotic effect of estrogen

雌激素抗动脉粥样硬化作用机制

• 批准号: 11470349
• 负责人: MORISHIGE Kenichiro
• 金额: $ 9.41万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470349/
• 关键词: estradiol; IMT; estrogen receptor; PDGF; eNOS; atherosclerosis; P-selection; パルスドップラー; 閉経; 脂質; P-セレクチン; IMT(intima media thickness); NOS; 血管内皮

Clinical study:Atherosclerotic cardiovascular disease (CVD) is the major cause of morbidity and mortality in postmenopausal women. Estrogens have been shown to inhibit atherosclerosis and to help maintaining arterial function.Measurement of intima-media thickness (IMT) of the carotid artery is used in pathophysiological studies of the atherosclerotic process to search the factors initiating the early development of atherosclerosis in the carotid arteries.IMT in the ERT group patients showed a significant decrease during HRT period in both mean and maximum IMT, while the control group patients showed no statistically significant change. Lipid metabolism markers and P-selection showed significant decrease in the longitudinal analysis. These data are under submission (Nishio et al.).In vitro study:In studies of human umbilical vein endotherial cells and SV40-transformed rat lung vascular endotherial cells, 17β-estradiol (E2), but not 17α-E2, caused acute activation of eNOS that was unaffected by actinomycin D and was specifically blocked by the pure estrogen receptor antagonist ICI-182,780. Furthermore, 17α-E2 induced eNOS activation through an Akt-dependent mechanism, which is mediated by Erαvia a nongenomic mechanism (Hisamoto et al.).In vascular smooth muscle cells, E2 suppressed PDGF-induced cell proliferation. But, the detailed mechanism of anti-proliferative effect of E2 is under investigation.

临床研究：动脉粥样硬化性心血管疾病（CVD）是绝经后妇女发病和死亡的主要原因。雌激素对动脉粥样硬化有抑制作用，有助于动脉功能的维持。颈动脉内膜-中层厚度（IMT）的测定可用于动脉粥样硬化的病理生理学研究，以寻找颈动脉粥样硬化早期发生的因素。雌激素替代治疗组患者的IMT在HRT期间显著降低，平均IMT和最大IMT均显著降低，而对照组患者的变化无统计学意义。脂代谢指标和P-选择素在纵向分析中显示显著降低。这些数据正在提交中（西尾等人）。体外研究：在对人脐静脉内皮细胞和SV 40转化的大鼠肺血管内皮细胞的研究中，17β-雌二醇（E2）（而非17α-E2）引起eNOS的急性激活，该激活不受放线菌素D的影响，并被纯雌激素受体拮抗剂ICI-182，780特异性阻断。此外，17α-E2通过Akt依赖性机制诱导eNOS活化，该机制由Erα通过非基因组机制介导（Hisamoto et al.）。在血管平滑肌细胞中，E2抑制PDGF诱导的细胞增殖。但是，E2抗增殖作用的详细机制仍在研究中。

项目成果

K Hisamoto, M Ohmichi, H Kurachi, J Hayakawa, Y Kanda, Y Nishio, K Adachi, K Tasaka, E Miyoshi, N Fujiwara, N Taniguchi, Y Murata: "Estrogen induces the Akt-dependent activation of endothelial nitric-oxide synthase in vascular endothelial cells"J Biol Che

K Hisamoto、M Ohmichi、H Kurachi、J Hayakawa、Y Kanda、Y Nishio、K Adachi、K Tasaka、E Miyoshi、N Fujiwara、N Taniguchi、Y Murata：“雌激素诱导内皮一氧化氮合酶的 Akt 依赖性激活

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