Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka-shi, Shizuoka 422-8526, Japan.
Atherosclerosis. 2011 Dec;219(2):545-51. doi: 10.1016/j.atherosclerosis.2011.08.051. Epub 2011 Sep 12.
Mechanisms underlying gender difference of atherogenesis were investigated focusing on direct effects of estrogen on the artery.
First, male and female apoE(-/-) mice were fed an atherogenic diet for 16 weeks from 10 weeks of age. Second, female apoE(-/-) mice were ovariectomized (ovx) or sham operated at 8 weeks of age, and 2-weeks afterwards, one-third of each ovx-group received conjugated equine estrogens (CEE) (0, 2.5 or 5.0 μg/day) for 16 weeks. Atherosclerotic lesions were examined after experimental periods. To clarify anti-atherogenic effect of 17β-estradiol (E2) on artery, neutral cholesteryl ester hydrolase (N-CEase) activity in aorta and peritoneal macrophages, and E2-treated J774A.1 cells were measured.
First, atherosclerotic lesion in female mice was significantly less than male mice without any changes in serum lipids and lipoprotein profile. N-CEase activity in aorta and peritoneal macrophages in female mice was significantly higher than male mice. Second, atherosclerotic lesion in ovx-group was significantly greater than sham-group. CEE-replacement to ovx-group decreased atherosclerotic lesion in a dose-dependent manner. N-CEase activity in aorta and peritoneal macrophages was decreased in ovx-group compared to sham-group, and restored by CEE-replacement in macrophages. To study detailed mechanisms, J774A.1 cells were treated with E2. E2 significantly increased N-CEase activity, and cAMP-dependent protein kinase (A-kinase) type II activity and the protein in cytosol fraction without any changes of total protein of A-kinase type II.
These results suggest that gender difference of atherogenesis is partly accounted for activation of N-CEase through estrogen-dependent translocation of A-kinase type II in macrophages.
本研究旨在探讨动脉粥样硬化形成中性别差异的机制，重点关注雌激素对动脉的直接作用。
首先，10 周龄雄性和雌性 apoE(-/-)小鼠喂食致动脉粥样硬化饮食 16 周。其次，8 周龄雌性 apoE(-/-)小鼠行卵巢切除术（ovx）或假手术，2 周后，每组三分之一的 ovx 小鼠接受结合雌激素（CEE）（0、2.5 或 5.0 μg/天）治疗 16 周。实验结束后检查动脉粥样硬化病变。为了阐明 17β-雌二醇（E2）对动脉的抗动脉粥样硬化作用，测量主动脉和腹腔巨噬细胞中的中性胆固醇酯水解酶（N-CEase）活性以及 E2 处理的 J774A.1 细胞。
首先，雌性小鼠的动脉粥样硬化病变明显少于雄性小鼠，而血清脂质和脂蛋白谱没有变化。雌性小鼠主动脉和腹腔巨噬细胞中的 N-CEase 活性明显高于雄性小鼠。其次，ovx 组的动脉粥样硬化病变明显大于 sham 组。CEE 替代治疗可剂量依赖性地减少 ovx 组的动脉粥样硬化病变。与 sham 组相比，ovx 组主动脉和腹腔巨噬细胞中的 N-CEase 活性降低，而 CEE 替代治疗可恢复巨噬细胞中的 N-CEase 活性。为了研究详细的机制，用 E2 处理 J774A.1 细胞。E2 可显著增加 N-CEase 活性和 cAMP 依赖性蛋白激酶（A-激酶）II 型活性以及细胞溶质部分的蛋白，而 A-激酶 II 型的总蛋白无变化。
这些结果表明，动脉粥样硬化形成中的性别差异部分归因于雌激素依赖性 A-激酶 II 的易位，导致巨噬细胞中 N-CEase 的激活。
