雌激素、选择性雌激素受体调节剂及一种选择性雌激素受体下调剂可抑制内皮细胞组织因子途径抑制物-1的生成。
Estrogens, selective estrogen receptor modulators, and a selective estrogen receptor down-regulator inhibit endothelial production of tissue factor pathway inhibitor 1.
作者信息
Dahm Anders E A, Iversen Nina, Birkenes Baard, Ree Anne Hansen, Sandset Per Morten
机构信息
Department of Haematology, Ullevål University Hospital, 0407 Oslo, Norway.
出版信息
BMC Cardiovasc Disord. 2006 Oct 9;6:40. doi: 10.1186/1471-2261-6-40.
BACKGROUND
Hormone therapy, oral contraceptives, and tamoxifen increase the risk of thrombotic disease. These compounds also reduce plasma content of tissue factor pathway inhibitor-1 (TFPI), which is the physiological inhibitor of the tissue factor pathway of coagulation. The current aim was to study if estrogens and estrogen receptor (ER) modulators may inhibit TFPI production in cultured endothelial cells and, if so, identify possible mechanisms involved.
METHODS
Human endothelial cell cultures were treated with 17beta-estradiol (E2), 17alpha-ethinylestradiol (EE2), tamoxifen, raloxifene, or fulvestrant. Protein levels of TFPI in cell media and cell lysates were measured by an enzyme-linked immunosorbent assay, and TFPI mRNA levels were assessed by quantitative PCR. Expression of ERalpha was analysed by immunostaining.
RESULTS
All compounds (each in a concentration of 10 nM) reduced TFPI in cell medium, by 34% (E2), 21% (EE2), 16% (tamoxifen), and 28% (raloxifene), respectively, with identical inhibitory effects on cellular TFPI levels. Expression of TFPI mRNA was principally unchanged. Treatment with fulvestrant, which was also associated with down-regulation of secreted TFPI (9% with 10 nM and 26% with 1000 nM), abolished the TFPI-inhibiting effect of raloxifene, but not of the other compounds. Notably, the combination of 1000 nM fulvestrant and 10 nM raloxifene increased TFPI secretion, and, conversely, 10 nM of either tamoxifen or raloxifene seemed to partly (tamoxifen) or fully (raloxifene) counteract the inhibitory effect of 1000 nM fulvestrant. The cells did not express the regular nuclear 66 kDa ERalpha, but instead a 45 kDa ERalpha, which was not regulated by estrogens or ER modulators.
CONCLUSION
E2, EE2, tamoxifen, raloxifene, and fulvestrant inhibited endothelial production of TFPI by a mechanism apparently independent of TFPI transcription.
背景
激素疗法、口服避孕药和他莫昔芬会增加血栓性疾病的风险。这些化合物还会降低组织因子途径抑制剂-1（TFPI）的血浆含量，而TFPI是凝血组织因子途径的生理性抑制剂。当前的目的是研究雌激素和雌激素受体（ER）调节剂是否会抑制培养的内皮细胞中TFPI的产生，如果是，则确定其中可能涉及的机制。
方法
用人内皮细胞培养物分别用17β-雌二醇（E2）、17α-乙炔雌二醇（EE2）、他莫昔芬、雷洛昔芬或氟维司群处理。通过酶联免疫吸附测定法测量细胞培养基和细胞裂解物中TFPI的蛋白水平，并通过定量PCR评估TFPI mRNA水平。通过免疫染色分析ERα的表达。
结果
所有化合物（每种浓度为10 nM）均降低了细胞培养基中的TFPI，分别降低了34%（E2）、21%（EE2）、16%（他莫昔芬）和28%（雷洛昔芬），对细胞内TFPI水平具有相同的抑制作用。TFPI mRNA的表达基本未改变。氟维司群处理也与分泌型TFPI的下调有关（10 nM时为9%，1000 nM时为26%），它消除了雷洛昔芬对TFPI的抑制作用，但对其他化合物没有作用。值得注意的是，1000 nM氟维司群和10 nM雷洛昔芬的组合增加了TFPI的分泌，相反，10 nM的他莫昔芬或雷洛昔芬似乎部分（他莫昔芬）或完全（雷洛昔芬）抵消了1000 nM氟维司群的抑制作用。这些细胞不表达常规的66 kDa核ERα，而是表达一种45 kDa的ERα，其不受雌激素或ER调节剂的调节。
结论
E2、EE2、他莫昔芬、雷洛昔芬和氟维司群通过一种明显独立于TFPI转录的机制抑制内皮细胞产生TFPI。
Zotero 插件