Kelly Daniel M, Sellers Donna J, Woodroofe M Nicola, Jones T Hugh, Channer Kevin S
a Biomedical Research Centre, Sheffield Hallam University , Sheffield, UK.
b Centre for Diabetes and Endocrinology, Barnsley Hospital NHS Foundation Trust , Barnsley, UK.
Endocr Res. 2013 Aug;38(3):125-138. doi: 10.3109/07435800.2012.735307. Epub 2012 Nov 20.
Low levels of serum testosterone in men are associated with cardiovascular disease. Clinical studies show that testosterone replacement therapy (TRT) can improve symptoms of cardiovascular disease and reduce the inflammatory burden evident in atherosclerosis.
We used an in vivo animal model to determine whether testosterone influences mediators of vascular inflammation as part of its beneficial effects on atherogenesis.
Testicular-feminized (Tfm) mice, which express low endogenous testosterone and a non-functional androgen receptor (AR), were used to assess the effect of androgen status on atheroma formation, serum lipids, and inflammatory mediators. Tfm mice were fed a high-cholesterol diet, received saline or physiological (TRT), and were compared to saline-treated XY littermates.
A total of 28 weeks of high-cholesterol diet caused fatty streak formation in the aortic root of XY littermates and Tfm mice, an effect significantly amplified in Tfm mice. Tfm mice on normal diet showed elevated serum tumor necrosis factor-α (TFN-α) and interleukin-6 compared to XY littermates. High-cholesterol diet induced increased monocyte chemoattractant protein-1 (MCP-1) in Tfm mice, and TFN-α and MCP-1 in XY littermates. TRT reduced fatty streak formation and serum interleukin-6 in Tfm mice but had no significant effects on lipid profiles. Monocyte/macrophage staining indicated local inflammation in aortic root fatty streak areas of all mice, with TRT reducing local inflammation through plaque reduction in Tfm mice. Fractalkine (CXCL1) and its receptor (CXCR1) were present in fatty streaks of all mice fed a high-cholesterol diet, independent of androgen status.
These results are consistent with AR-dependent and AR-independent anti-inflammatory actions of testosterone in atheroprotection, although the local anti-inflammatory mechanisms via which testosterone acts remain unknown.
男性血清睾酮水平低与心血管疾病相关。临床研究表明，睾酮替代疗法（TRT）可改善心血管疾病症状，并减轻动脉粥样硬化中明显的炎症负担。
我们使用体内动物模型来确定睾酮是否会影响血管炎症介质，这是其对动脉粥样硬化形成有益作用的一部分。
睾丸雌性化（Tfm）小鼠内源性睾酮表达低且雄激素受体（AR）无功能，用于评估雄激素状态对动脉粥样硬化形成、血脂和炎症介质的影响。给Tfm小鼠喂食高胆固醇饮食，给予生理盐水或生理剂量的睾酮（TRT），并与接受生理盐水处理的XY同窝小鼠进行比较。
共28周的高胆固醇饮食导致XY同窝小鼠和Tfm小鼠主动脉根部出现脂肪条纹形成，这种效应在Tfm小鼠中显著增强。与XY同窝小鼠相比，正常饮食的Tfm小鼠血清肿瘤坏死因子-α（TFN-α）和白细胞介素-6升高。高胆固醇饮食诱导Tfm小鼠单核细胞趋化蛋白-1（MCP-1）增加，XY同窝小鼠中TFN-α和MCP-1增加。TRT减少了Tfm小鼠的脂肪条纹形成和血清白细胞介素-6，但对血脂水平无显著影响。单核细胞/巨噬细胞染色显示所有小鼠主动脉根部脂肪条纹区域存在局部炎症，TRT通过减少Tfm小鼠的斑块来减轻局部炎症。趋化因子（CXCL1）及其受体（CXCR1）存在于所有喂食高胆固醇饮食小鼠的脂肪条纹中，与雄激素状态无关。
这些结果与睾酮在动脉粥样硬化保护中的AR依赖性和AR非依赖性抗炎作用一致，尽管睾酮发挥作用的局部抗炎机制尚不清楚。
