Bourghardt Johan, Bergström Göran, Krettek Alexandra, Sjöberg Sara, Borén Jan, Tivesten Asa
Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at Göteborg University, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden.
Endocrinology. 2007 Sep;148(9):4128-32. doi: 10.1210/en.2007-0259. Epub 2007 Apr 19.
Estradiol, the major endogenous estrogen, reduces experimental atherosclerosis and metabolizes to 2-methoxyestradiol in vascular cells. Currently undergoing evaluation in clinical cancer trials, 2-methoxyestradiol potently inhibits cell proliferation independently of the classical estrogen receptors. This study examined whether 2-methoxyestradiol affects atherosclerosis development in female mice. Apolipoprotein E-deficient mice, a well-established mouse model of atherosclerosis, were ovariectomized and treated through slow-release pellets with placebo, 17beta-estradiol (6 microg/d), or 2-methoxyestradiol [6.66 microg/d (low-dose) or 66.6 microg/d (high-dose)]. After 90 d, body weight gain decreased and uterine weight increased in the high-dose but not low-dose 2-methoxyestradiol group. En face analysis showed that the fractional area of the aorta covered by atherosclerotic lesions decreased in the high-dose 2-methoxyestradiol (52%) but not in the low-dose 2-methoxyestradiol group. Total serum cholesterol levels decreased in the high- and low-dose 2-methoxyestradiol groups (19%, P < 0.05 and 21%, P = 0.062, respectively). Estradiol treatment reduced the fractional atherosclerotic lesion area (85%) and decreased cholesterol levels (42%). In conclusion, our study shows for the first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in vivo. The antiatherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity may argue that trials on cardiovascular effects of hormone replacement therapy should use estradiol rather than other estrogens. Future research should define the role of 2-methoxyestradiol as a mediator of the antiatherosclerotic actions of estradiol. Furthermore, evaluation of the effects of 2-methoxyestradiol on cardiovascular disease endpoints in ongoing clinical trials is of great interest.
雌二醇是主要的内源性雌激素，可减轻实验性动脉粥样硬化，并在血管细胞中代谢为2-甲氧基雌二醇。2-甲氧基雌二醇目前正在临床癌症试验中进行评估，它能独立于经典雌激素受体有效抑制细胞增殖。本研究检测了2-甲氧基雌二醇是否影响雌性小鼠的动脉粥样硬化发展。载脂蛋白E缺陷小鼠是一种成熟的动脉粥样硬化小鼠模型，将其卵巢切除后，通过缓释微丸给予安慰剂、17β-雌二醇（6微克/天）或2-甲氧基雌二醇[6.66微克/天（低剂量）或66.6微克/天（高剂量）]进行治疗。90天后，高剂量而非低剂量2-甲氧基雌二醇组的体重增加减少，子宫重量增加。正面分析显示，高剂量2-甲氧基雌二醇组（52%）主动脉粥样硬化病变覆盖的部分面积减少，而低剂量2-甲氧基雌二醇组未减少。高剂量和低剂量2-甲氧基雌二醇组的总血清胆固醇水平均降低（分别为19%，P<0.05和21%，P = 0.062）。雌二醇治疗可减少动脉粥样硬化病变部分面积（85%）并降低胆固醇水平（42%）。总之，我们的研究首次表明2-甲氧基雌二醇可在体内减少动脉粥样硬化病变形成。一种缺乏雌激素受体激活能力的雌二醇代谢产物的抗动脉粥样硬化活性可能表明，激素替代疗法对心血管影响的试验应使用雌二醇而非其他雌激素。未来的研究应明确2-甲氧基雌二醇作为雌二醇抗动脉粥样硬化作用介质的作用。此外，评估2-甲氧基雌二醇在正在进行的临床试验中对心血管疾病终点的影响具有重要意义。
