The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China; Department of Critical Care Medicine, Tengzhou Central People's Hospital, Tengzhou, Shandong, China.
Exp Gerontol. 2019 May;119:128-137. doi: 10.1016/j.exger.2019.01.029. Epub 2019 Jan 30.
Androgen has been implicated in aging-related cardiac remodeling, but its precise role in aging heart remains controversial. We aimed to investigate the role of testosterone in the development of aging-related cardiac remodeling and the mechanisms involved.
Wild type and Axl knockout mice (Axl) were randomized into three groups: the young group (n = 30, 3 months old), the aging group (n = 30, 18 months old), the testosterone undecanoate treatment group (TU, n = 30, 18 months old). Mice in the TU group were given testosterone undecanoate (39 mg/kg) by subcutaneous injection on the back at fifteen-months-old, once a month, a total of three times. The old group received solvent reagent (corn oil) by the same method.
The aging mice exhibited a decrease in serum testosterone, and Gas6 levels and an increase in apoptosis, and manifested cardiac fibrosis. Testosterone injection to wild type mice increased the levels of testosterone and Gas6 in serum and decreased cardiac apoptosis and fibrosis. Axlmice receiving testosterone injection exhibited no obvious improvement in cardiac remodeling although the levels of testosterone and Gas6 in serum elevated.
These data indicated that testosterone replacement therapy (TRT) alleviates cardiac fibrosis and apoptosis, at least in part by enhancing Gas6 expression. Moreover, deletion of Axl disables testosterone, which indicated that Axl is an important downstream regulator of testosterone. TRT would improve aging-related cardiac remolding via Gas6/Axl signaling pathway, implicating its therapeutic potential to treat aging-related heart disease.
雄激素与衰老相关的心脏重构有关，但它在衰老心脏中的确切作用仍存在争议。我们旨在研究睾酮在衰老相关心脏重构中的作用及其相关机制。
将野生型和 Axl 敲除小鼠（Axl）随机分为三组：年轻组（n=30，3 个月龄）、衰老组（n=30，18 个月龄）和睾酮十一酸酯治疗组（TU，n=30，18 个月龄）。TU 组的小鼠在 15 个月龄时背部皮下注射睾酮十一酸酯（39mg/kg），每月一次，共三次。衰老组给予相同方法的溶剂试剂（玉米油）。
衰老小鼠血清睾酮、Gas6 水平下降，凋亡增加，表现出心肌纤维化。向野生型小鼠注射睾酮可增加血清中睾酮和 Gas6 的水平，减少心脏凋亡和纤维化。虽然血清中睾酮和 Gas6 的水平升高，但接受睾酮注射的 Axl 小鼠的心脏重构无明显改善。
这些数据表明，睾酮替代疗法（TRT）可减轻心脏纤维化和凋亡，至少部分是通过增强 Gas6 表达来实现的。此外，Axl 的缺失使睾酮失活，表明 Axl 是睾酮的重要下游调节剂。TRT 通过 Gas6/Axl 信号通路改善衰老相关的心脏重塑，暗示其治疗衰老相关心脏病的潜力。
