Dihydrotestosterone Suppresses Foam Cell Formation and Attenuates Atherosclerosis Development
Dihydrotestosterone Suppresses Foam Cell Formation and Attenuates Atherosclerosis Development
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DOI：
10.1210/en.2009-1268
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发表时间：
2010-07-01
期刊：
影响因子：
4.8
通讯作者：
Nawata, Hajime
中科院分区：
文献类型：
--
作者：
Qiu, Yang;Yanase, Toshihiko;Nawata, Hajime
睾酮在动脉粥样硬化中的作用仍然不清楚，因为它被芳香化为雌激素。我们研究了非芳香化的天然雄激素5 α-二氢睾酮（DHT）对兔动脉粥样硬化形成的影响与促动脉粥样硬化分子凝集素样氧化低密度脂蛋白受体-1（LOX-1）及其下游分子的关系。将39只雄性新西兰白色家兔分为4组：1）正常饲料非去势组（n = 6）; 2）高胆固醇饲料（HCD）非去势组（n = 10）; 3）HCD + sc安慰剂颗粒去势组（n = 11）; 4）HCD + sc 150 mg DHT颗粒去势组（n = 12）。在去势时植入sc DHT或安慰剂颗粒。去势或假手术后，喂饲HCD 8 wk，测量整个主动脉的斑块面积。HCD诱导的斑块面积增加在去势加安慰剂组中最严重，在去势加DHT组中减弱。近端降主动脉的显微镜检查显示，与安慰剂组相比，DHT显著减少了HCD诱导的泡沫细胞形成，泡沫细胞主要由内膜层中的巨噬细胞组成。DHT处理的泡沫细胞的积累减少伴随着这些细胞中LOX-1 mRNA表达的显着减少。在从表达雄激素受体（AR）的雄性野生型小鼠制备的培养巨噬细胞中，1 × 10（-8）M和1 × 10（-9）M DHT抑制氧化低密度脂蛋白诱导的泡沫细胞的形成。此外，在培养的巨噬细胞LOX-1和炎症细胞因子的表达显着抑制DHT。这种抑制作用的DHT泡沫细胞的形成和细胞因子的表达，没有观察到在培养的巨噬细胞制备的雄性AR无效的小鼠，这表明参与AR的机制。结论：生理水平的二氢睾酮通过抑制巨噬细胞内膜泡沫细胞的形成，部分通过抑制LOX-1的表达，从而减轻兔动脉粥样硬化的发展。（内分泌学151：3307-3316，2010）
The role of testosterone in atherosclerosis remains unclear because it is aromatized to estrogen. We investigated the effect of the nonaromatized natural androgen 5 alpha-dihydrotestosterone (DHT) on the rabbit atherogenesis in relation to the proatherogenic molecule lectin-like oxidized-low-density lipoprotein receptor-1 (LOX-1) and its downstream molecules. Thirty-nine male New Zealand white rabbits were divided into four groups: 1) noncastrated group with normal chow diet (n = 6); 2) noncastrated group with high-cholesterol diet (HCD) (n = 10); 3) castrated group with HCD plus sc placebo pellet (n = 11); and 4) castrated group with HCD plus sc 150 mg DHT pellet (n = 12). Implantation of sc DHT or placebo pellet was performed at the time of castration. After castration or sham operation, the rabbits were fed the HCD for 8 wk, and plaque areas were assessed in the entire aorta. The HCD-induced increase in plaque area, which was most aggravated in the castration plus placebo group, was attenuated in the castration plus DHT group. Microscopic examination of the proximal descending aorta revealed that DHT significantly reduced HCD-induced foam cell formation, which was mostly composed of macrophages in the intima layer, compared with the placebo group. The decreased accumulation of foam cells with DHT treatment was accompanied by a marked reduction in the expression of LOX-1 mRNA in these cells. In cultured macrophages prepared from male wild-type mice that express the androgen receptor (AR), 1 x 10(-8) M and 1 x 10(-9) M DHT inhibited the formation of foam cells induced by oxidized low-density lipoprotein. Moreover, the expression of LOX-1 and inflammatory cytokines in the cultured macrophages was significantly suppressed by DHT. Such suppressive effects of DHT on foam cell formation and cytokine expression were not observed in cultured macrophages prepared from male AR-null mice, suggesting an involvement of AR in the mechanism. In conclusion, physiological levels of DHT attenuated the development of atherosclerosis in rabbits through the suppression of intimal foam cell formation of macrophage partly via the suppression of LOX-1 expression. (Endocrinology 151: 3307-3316, 2010)