Dubey Raghvendra K, Gillespie Delbert G, Grögli Marion, Kloosterboer Helenius J, Imthurn Bruno
Department of Medicine, Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.
J Clin Endocrinol Metab. 2004 Feb;89(2):852-9. doi: 10.1210/jc.2003-031272.
Tibolone, a hormone replacement drug, protects postmenopausal women against osteoporosis and climacteric symptoms without inducing adverse effects on the endometrium and breast. Compared with other estrogens, little is known about the cardiovascular effects of tibolone. Because abnormal growth of smooth muscle cells (SMCs) is a prerequisite for coronary artery disease, here we investigated the effects of tibolone on SMC growth. We examined the effects of tibolone and its metabolites on human arterial SMC growth (DNA synthesis, cellular proliferation, cell migration, collagen synthesis) and MAPK expression. Fetal calf serum-induced SMC growth, phosphorylated MAPK expression, and platelet-derived growth factor-induced SMC-migration were concentration-dependently inhibited by tibolone and its endogenous estrogenic and progestogenic/androgenic metabolites in the following order of potency: Delta 4-tibolone>3 beta-OH-tibolone congruent with 3 alpha-OH-tibolone. The antimitogenic effects of tibolone were partially blocked by ER antagonist (ICI182780), progesterone receptor antagonist (RU486) but not by the androgen receptor antagonist (flutamide); moreover, RU486 was more potent than ICI182780. The antimitogenic effects of tibolone were completely blocked by RU486 plus ICI182780. In addition, the inhibitory effects of equimolar concentrations of the three tibolone metabolites summed up to the inhibitory effects of tibolone. In conclusion, tibolone inhibits SMC growth and MAPK phosphorylation via both its estrogenic and progestogenic metabolites, and these inhibitory effects involve both progesterone and ERs. Hence, tibolone may induce antivasoocclusive actions and protect women against coronary artery disease.
替勃龙是一种激素替代药物，可保护绝经后女性免受骨质疏松症和更年期症状的困扰，且不会对子宫内膜和乳腺产生不良影响。与其他雌激素相比，关于替勃龙对心血管系统的影响知之甚少。由于平滑肌细胞（SMC）的异常生长是冠状动脉疾病的一个先决条件，因此我们在此研究了替勃龙对SMC生长的影响。我们检测了替勃龙及其代谢产物对人动脉SMC生长（DNA合成、细胞增殖、细胞迁移、胶原蛋白合成）和丝裂原活化蛋白激酶（MAPK）表达的影响。胎牛血清诱导的SMC生长、磷酸化MAPK表达以及血小板衍生生长因子诱导的SMC迁移均受到替勃龙及其内源性雌激素和孕激素/雄激素代谢产物的浓度依赖性抑制，其效力顺序如下：Δ4-替勃龙>3β-羟基替勃龙≈3α-羟基替勃龙。替勃龙的抗增殖作用部分被雌激素受体拮抗剂（ICI182780）、孕激素受体拮抗剂（RU486）阻断，但未被雄激素受体拮抗剂（氟他胺）阻断；此外，RU486比ICI182780更有效。替勃龙的抗增殖作用被RU486加ICI182780完全阻断。此外，等摩尔浓度的三种替勃龙代谢产物的抑制作用之和等于替勃龙的抑制作用。总之，替勃龙通过其雌激素和孕激素代谢产物抑制SMC生长和MAPK磷酸化，且这些抑制作用涉及孕激素和雌激素受体。因此，替勃龙可能诱导抗血管闭塞作用并保护女性免受冠状动脉疾病的侵害。
