Department of Cardiology, Nangfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Braz J Med Biol Res. 2011 Nov;44(11):1118-24. doi: 10.1590/s0100-879x2011007500128. Epub 2011 Sep 30.
The testicular feminized (Tfm) mouse carries a nonfunctional androgen receptor (AR) and reduced circulating testosterone levels. We used Tfm and castrated mice to determine whether testosterone modulates markers of aging in cardiomyocytes via its classic AR-dependent pathway or conversion to estradiol. Male littermates and Tfm mice were divided into 6 experimental groups. Castrated littermates (group 1) and sham-operated Tfm mice (group 2, N = 8 each) received testosterone. Sham-operated Tfm mice received testosterone in combination with the aromatase inhibitor anastrazole (group 3, N = 7). Castrated littermates (group 4) and sham-operated untreated Tfm mice (group 5) were used as controls (N = 8 and 7, respectively). An additional control group (group 6) consisted of age-matched non-castrated littermates (N = 8). Cardiomyocytes were isolated from the left ventricle, telomere length was measured by quantitative PCR and expression of p16INK4α, retinoblastoma (Rb) and p53 proteins was detected by Western blot 3 months after treatment. Compared with group 6, telomere length was short (P < 0.01) and expression of p16INK4α, Rb and p53 proteins was significantly (P < 0.05) up-regulated in groups 4 and 5. These changes were improved to nearly normal levels in groups 1 and 2 (telomere length = 0.78 ± 0.05 and 0.80 ± 0.08; p16INK4α = 0.13 ± 0.03 and 0.15 ± 0.04; Rb = 0.45 ± 0.05 and 0.39 ± 0.06; p53 = 0.16 ± 0.04 and 0.13 ± 0.03), but did not differ between these two groups. These improvements were partly inhibited in group 3 compared with group 2 (telomere length = 0.65 ± 0.08 vs 0.80 ± 0.08, P = 0.021; p16INK4α = 0.28 ± 0.05 vs 0.15 ± 0.04, P = 0.047; Rb = 0.60 ± 0.06 vs 0.39 ± 0.06, P < 0.01; p53 = 0.34 ± 0.06 vs 0.13 ± 0.03, P = 0.004). In conclusion, testosterone deficiency contributes to cardiomyocyte aging. Physiological testosterone can delay cardiomyocyte aging via an AR-independent pathway and in part by conversion to estradiol.
睾丸女性化（Tfm）小鼠携带非功能性雄激素受体（AR），并降低循环中的睾丸激素水平。我们使用 Tfm 和去势小鼠来确定睾丸激素是否通过其经典的 AR 依赖途径或转化为雌二醇来调节心肌细胞的衰老标志物。雄性同窝仔鼠被分为 6 个实验组。去势同窝仔鼠（第 1 组）和假手术 Tfm 小鼠（第 2 组，每组 8 只）接受睾丸激素治疗。假手术 Tfm 小鼠接受睾丸激素和芳香酶抑制剂阿那曲唑（第 3 组，每组 7 只）联合治疗。去势同窝仔鼠（第 4 组）和未治疗的假手术 Tfm 小鼠（第 5 组）作为对照（每组 8 只和 7 只）。另外一组对照组（第 6 组）由年龄匹配的未去势同窝仔鼠组成（每组 8 只）。治疗 3 个月后，从左心室分离心肌细胞，通过实时定量 PCR 测量端粒长度，并通过 Western blot 检测 p16INK4α、视网膜母细胞瘤（Rb）和 p53 蛋白的表达。与第 6 组相比，第 4 组和第 5 组的端粒长度明显缩短（P<0.01），p16INK4α、Rb 和 p53 蛋白的表达显著上调（P<0.05）。第 1 组和第 2 组的这些变化被改善到接近正常水平（端粒长度=0.78±0.05 和 0.80±0.08；p16INK4α=0.13±0.03 和 0.15±0.04；Rb=0.45±0.05 和 0.39±0.06；p53=0.16±0.04 和 0.13±0.03），但两组之间没有差异。与第 2 组相比，第 3 组的这些改善部分受到抑制（端粒长度=0.65±0.08 与 0.80±0.08，P=0.021；p16INK4α=0.28±0.05 与 0.15±0.04，P=0.047；Rb=0.60±0.06 与 0.39±0.06，P<0.01；p53=0.34±0.06 与 0.13±0.03，P=0.004）。综上所述，睾丸激素缺乏会导致心肌细胞衰老。生理睾丸激素可通过 AR 非依赖性途径和部分转化为雌二醇来延缓心肌细胞衰老。
