New therapy via targeting androgen receptor in monocytes/macrophages to battle atherosclerosis.
New therapy via targeting androgen receptor in monocytes/macrophages to battle atherosclerosis.
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DOI：
10.1161/hypertensionaha.113.02804
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发表时间：
2014-06
期刊：
影响因子：
--
通讯作者：
Chang C
中科院分区：
文献类型：
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作者：
Huang CK;Pang H;Wang L;Niu Y;Luo J;Chang E;Sparks JD;Lee SO;Chang C
男性患冠状动脉疾病（CAD）包括动脉粥样硬化的风险更高。雄激素受体（AR）在几种与动脉粥样硬化相关的细胞类型中表达，包括单核/巨噬细胞、内皮细胞（ECs）和平滑肌细胞（SMCs），但其在每种细胞类型中在动脉粥样硬化病变发展过程中的病理生理作用尚不清楚。使用Cre-loxP系统，我们选择性地敲除这三种细胞类型中的AR，然后将产生的ARKO小鼠，单核/巨噬细胞ARKO (MARKO), EC-ARKO （EARKO）和SMC-ARKO （SARKO）与低密度脂蛋白受体（LDLR）缺陷（LDLR - / -）小鼠杂交，培养出MARKO-LDLR - / -， EARKO-LDLR - / -和SARKO-LDLR - / -小鼠，用于动脉粥样硬化的研究。结果表明，与野生型（WT-LDLR - / -）对照小鼠相比，MARKO-LDLR - / -小鼠的动脉粥样硬化程度降低。然而，在EARKO-LDLR - / -和SARKO-LDLR - / -小鼠中，与WT-LDLR - / -小鼠相比，未检测到显著差异，这表明AR在单核/巨噬细胞中发挥主要作用，而不是在ECs和SMCs中。分子机制解剖提示，AR在单核/巨噬细胞中上调TNF-α、ITGβ2和LOX-1分子，这些分子参与动脉粥样硬化中与炎症相关的3个主要过程，包括单核/巨噬细胞向HUVECs细胞的迁移和粘附，以及随后的泡沫细胞形成。在WT-LDLR - / -小鼠中，通过AR降解增强剂ASC-J9®靶向AR，与在MARKO-LDLR - / -小鼠中观察到的效果相似，对脂质谱几乎没有影响。总之，单核/巨噬细胞中的AR在动脉粥样硬化中起关键作用，用ASC-J9®靶向AR可能是对抗动脉粥样硬化的一种新的潜在治疗方法。
The male gender has a higher risk to develop the coronary artery diseases (CAD) including atherosclerosis. The androgen receptor (AR) is expressed in several atherosclerosis associated cell types, including monocytes/macrophages, endothelial cells (ECs), and smooth muscle cells (SMCs), but its pathophysiological role in each cell type during the development of atherosclerotic lesions remains unclear. Using the Cre-loxP system, we selectively knocked out AR in these three cell types and the resultant ARKO mice, monocyte/macrophage ARKO (MARKO), EC-ARKO (EARKO), and SMC-ARKO (SARKO), were then crossed with the low density lipoprotein receptor (LDLR) deficient (LDLR−/−) mice to develop MARKO-LDLR−/−, EARKO-LDLR−/−, and SARKO-LDLR−/− mice for the study of atherosclerosis. The results showed that the MARKO-LDLR−/− mice had reduced atherosclerosis compared to the wild type (WT-LDLR−/−) control mice. However, no significant difference was detected in EARKO-LDLR−/− and SARKO-LDLR−/− mice compared to WT-LDLR−/− mice, suggesting that the AR in monocytes/macrophages, and not in ECs and SMCs, plays a major role to promote atherosclerosis. Molecular mechanism dissection suggested that AR in monocytes/macrophages up-regulated the TNF-α, ITGβ2, and LOX-1 molecules that are involved in 3 major inflammation related processes in atherosclerosis, including monocytes/macrophages migration and adhesion to HUVECs cells, and subsequent foam cell formation. Targeting AR via the AR degradation enhancer, ASC-J9®, in WT-LDLR−/− mice showed similar effects as seen in MARKO-LDLR−/− mice with little influence on lipid profile. In conclusion, the AR in monocytes/macrophages plays key roles in atherosclerosis and targeting AR with ASC-J9® may represent a new potential therapeutic approach to battle atherosclerosis.