Deterioration of atherosclerosis in mice lacking angiotensin II type 1A receptor in bone marrow-derived cells
Deterioration of atherosclerosis in mice lacking angiotensin II type 1A receptor in bone marrow-derived cells
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DOI：
10.1038/labinvest.2008.42
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发表时间：
2008-07-01
影响因子：
5
通讯作者：
Fukamizu, Akiyoshi
中科院分区：
文献类型：
--
作者：
Kato, Hideki;Ishida, Junji;Fukamizu, Akiyoshi
肾素-血管紧张素系统（RAS）调节终末器官损伤，导致心血管和肾脏疾病。体外和体内实验均表明，血管紧张素II（Ang II）1型（AT 1）受体途径也对骨髓源性细胞（BMDC）发挥促炎和促动脉粥样硬化作用。在这里，我们研究如何AT1受体表达BMDCs有助于动脉粥样硬化和肾损伤在体内移植骨髓到RAS激活的转基因小鼠。接受缺乏血管紧张素II 1a型受体（AT1a）基因突变小鼠骨髓移植的小鼠和接受野生型（WT）小鼠移植的小鼠之间的肾损伤程度没有差异。然而，接受来自AT 1a "敲除"（KO）小鼠的移植的小鼠显示出加速的致死性和动脉粥样硬化病变。提示AT1a受体对BMDCs的作用具有器官依赖性。AT1a-KO小鼠巨噬细胞的微阵列表达谱显示，动脉粥样硬化相关基因的mRNA水平发生了显著变化。根据体内动脉粥样硬化结果，AT1a-KO巨噬细胞相对于WT小鼠的巨噬细胞表现出更大的修饰脂蛋白摄取。我们认为，AT1a受体的表达BMDCs限制动脉粥样硬化在体内。
The renin-angiotensin system (RAS) modulates end-organ damages, resulting in cardiovascular and kidney diseases. Experiments both in vitro and in vivo demonstrate that the angiotensin II (Ang II) type 1 (AT1) receptor pathway also exerts pro-inflammatory and pro-atherogenic effects on bone marrow-derived cells (BMDCs). Here, we investigated how AT1 receptor expression by BMDCs contributes to atherosclerosis and kidney injury in vivo by transplanting BM into RAS-activated transgenic mice. There was no difference in the extent of kidney damage between mice receiving BM transplants from mutant mice lacking the angiotensin II type 1a receptor (AT1a) gene and mice receiving transplants from wild-type (WT) mice. However, mice receiving transplants from AT1a 'knockout' (KO) mice displayed accelerated lethality and atherosclerotic lesions. These results indicated that the effects of AT1a receptor on BMDCs are organ dependent. Microarray expression profiling of macrophages from AT1a-KO mice revealed significant changes in the mRNA levels for a number of genes implicated in atherosclerosis. In accordance with the in vivo atherosclerosis results, AT1a-KO macrophages exhibited greater uptake of modified lipoproteins relative to macrophages from WT mice. We propose that the expression of AT1a receptor by BMDCs limits atherosclerosis in vivo.