Mukherjee Tapan K, Dinh Hillary, Chaudhuri Gautam, Nathan Lauren
Department of Obstetrics and Gynecology, University of California Los Angeles School of Medicine, Los Angeles, CA 90095-1740, USA.
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):4055-60. doi: 10.1073/pnas.052703199.
We previously reported that testosterone attenuated atherogenesis in LDLR(-/-) male mice, and that this effect of testosterone was most likely caused by its conversion to estradiol. Estradiol inhibits vascular cell adhesion molecule-1 (VCAM-1) expression, and expression of VCAM-1 is one of the early events in atherogenesis. We assessed the cellular mechanism(s) involved by which testosterone attenuates atherogenesis. We evaluated whether testosterone inhibited TNFalpha-induced VCAM-1 expression via its conversion to estradiol by the enzyme aromatase in human umbilical vein endothelial cells (HUVEC). Aromatase mRNA was dedected by reverse transcription-PCR in these cells. Testosterone (30 nM-1 microM) attenuated VCAM-1 mRNA expression in a concentration-dependent manner. The non aromatizable androgen, dihydrotestosterone, had no effect on VCAM-1 mRNA expression. Testosterone was less effective in attenuating VCAM-1 expression in the presence of anastrozole, an inhibitor of aromatase, indicating that testosterone inhibited VCAM-1 via conversion to estradiol. Estradiol also attenuated VCAM-1 mRNA expression, but this action was not abolished in the presence of anastrozole, indicating that anastrozole itself did not modulate VCAM-1 mRNA expression. The effect of testosterone on VCAM-1 mRNA expression was inhibited in the presence of the estrogen receptor antagonist, ICI-182780. Testosterone also attenuated TNFalpha-induced VCAM-1 protein expression, and this attenuation was abolished in the presence of anastrozole. In conclusion, testosterone inhibited VCAM-1 mRNA and protein expression in HUVEC by its conversion to estradiol via the enzyme aromatase present in the endothelial cells. Results from our study may help explain the mechanism by which testosterone may have beneficial effects on the cardiovascular system.
我们之前报道过，睾酮可减轻低密度脂蛋白受体基因敲除（LDLR(-/-)）雄性小鼠的动脉粥样硬化形成，且睾酮的这种作用很可能是由其转化为雌二醇所致。雌二醇可抑制血管细胞黏附分子-1（VCAM-1）的表达，而VCAM-1的表达是动脉粥样硬化形成的早期事件之一。我们评估了睾酮减轻动脉粥样硬化形成所涉及的细胞机制。我们研究了睾酮是否通过人脐静脉内皮细胞（HUVEC）中的芳香化酶将其转化为雌二醇，从而抑制肿瘤坏死因子α（TNFα）诱导的VCAM-1表达。通过逆转录聚合酶链反应（RT-PCR）检测这些细胞中的芳香化酶mRNA。睾酮（30 nM - 1 μM）以浓度依赖的方式减轻VCAM-1 mRNA的表达。不可芳香化的雄激素双氢睾酮对VCAM-1 mRNA的表达没有影响。在芳香化酶抑制剂阿那曲唑存在的情况下，睾酮减轻VCAM-1表达的效果减弱，这表明睾酮通过转化为雌二醇来抑制VCAM-1。雌二醇也可减轻VCAM-1 mRNA的表达，但在阿那曲唑存在时这种作用并未消除，这表明阿那曲唑本身不会调节VCAM-1 mRNA的表达。在雌激素受体拮抗剂ICI-182780存在的情况下，睾酮对VCAM-1 mRNA表达的作用受到抑制。睾酮还可减轻TNFα诱导的VCAM-1蛋白表达，且在阿那曲唑存在时这种减轻作用消失。总之，睾酮通过内皮细胞中存在的芳香化酶将其转化为雌二醇，从而抑制HUVEC中VCAM-1的mRNA和蛋白表达。我们的研究结果可能有助于解释睾酮对心血管系统产生有益作用的机制。
