Inhibition of RORα/γ suppresses atherosclerosis via inhibition of both cholesterol absorption and inflammation.
Inhibition of RORα/γ suppresses atherosclerosis via inhibition of both cholesterol absorption and inflammation.
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DOI：
10.1016/j.molmet.2016.07.001
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发表时间：
2016-10
影响因子：
8.1
通讯作者：
Burris TP
中科院分区：
文献类型：
--
作者：
Billon C;Sitaula S;Burris TP
心血管疾病（CVD）是西方国家死亡的主要原因。动脉粥样硬化是一种多步骤的炎症性疾病，其特征在于在早期阶段，胆固醇在动脉壁中积累，随后招募免疫细胞。我们试图确定药物抑制RORα/γ活性是否有利于动脉粥样硬化的治疗。为了确定RORα和RORγ在动脉粥样硬化中的作用，我们使用了LDL-R−/−小鼠动脉粥样硬化模型，该模型被置于高胆固醇饮食中，并用SR 1001（一种RORα/γ反向激动剂）治疗四周。我们的研究结果表明，ROR反向激动剂的治疗大大减少了体内斑块的形成。抑制RORα/γ活性的抗动脉粥样硬化活性的机制似乎是由于靶向两个不同的途径。SR 1001治疗通过增加肠道胆固醇排泄降低血浆低密度脂蛋白（LDL）水平，而不影响高密度脂蛋白（HDL）。SR 1001治疗还诱导了抗动脉粥样硬化免疫特征，其特征在于Th 17细胞减少和Treg和Th 2细胞增加。我们的数据表明，RORα和RORγ在动脉粥样硬化的发展中起着关键作用，通过调节至少两个重要的途径在这种疾病的病理学：胆固醇流量和炎症。我们的数据表明，RORα/γ的药理学靶向可能是治疗动脉粥样硬化的有效方法，提供了相对于他汀类药物的独特作用机制。SR 1001在LDL-R−/−小鼠模型中减少动脉粥样硬化的发展。SR 1001在动脉粥样硬化背景下促进Treg和Th 2并降低Th 17细胞分化。SR 1001增强肠道胆固醇排泄。
Cardiovascular diseases (CVDs) are the leading cause of mortality in Western countries. Atherosclerosis is a multi-step inflammatory disease characterized at early stages by accumulation of cholesterol in the arterial wall followed by recruitment of immune cells. We sought to determine if pharmacological suppression of RORα/γ activity is beneficial in treatment of atherosclerosis. To identify the role of RORα and RORγ in atherosclerosis, we used the LDL-R−/− mouse model of atherosclerosis placed on a high cholesterol diet treated with SR1001, a RORα/γ inverse agonist, for four weeks. Our results demonstrate that treatment with the ROR inverse agonist substantially decreases plaque formation in vivo. The mechanism of the anti-atherogenic activity of the inhibition of RORα/γ activity appeared to be due to targeting two distinct pathways. SR1001 treatment reduced plasma low density lipoprotein (LDL) level without affecting high density lipoprotein (HDL) via increasing intestinal cholesterol excretion. Treatment with SR1001 also induced an anti-atherogenic immune profile that was characterized by a reduction in Th17 cells and an increase in Treg and Th2 cells. Our data suggest that RORα and RORγ play a critical role in atherosclerosis development by regulating at least two major pathways important in the pathology of this disease: cholesterol flux and inflammation. Our data suggest that pharmacological targeting of RORα/γ may be an effective method for treatment of atherosclerosis offering a distinct mechanism of action relative to statins. SR1001 decreases atherosclerosis development in a LDL-R−/− mouse model. SR1001 promotes Treg and Th2 and decreases Th17 cells differentiation in an atherosclerotic context. SR1001 enhances intestinal cholesterol excretion.
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影响因子：
82.9
作者：
Ait-Oufella, H;Salomon, BL;Mallat, Z
通讯作者：
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影响因子：
4.6
作者：
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通讯作者：
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影响因子：
8.2
作者：
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影响因子：
32.4
作者：
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通讯作者：
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DOI：
10.1073/pnas.97.18.10132
发表时间：
2000-08-29
影响因子：
11.1
作者：
Kurebayashi, S;Ueda, E;Jetten, AM
通讯作者：
Jetten, AM