11β-hydroxysteroid dehydrogenase type 2 deficiency accelerates atherogenesis and causes proinflammatory changes in the endothelium in apoe-/- mice.
11β-hydroxysteroid dehydrogenase type 2 deficiency accelerates atherogenesis and causes proinflammatory changes in the endothelium in apoe-/- mice.
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DOI：
10.1210/en.2010-0925
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发表时间：
2011-01
期刊：
影响因子：
4.8
通讯作者：
Kotelevtsev YV
中科院分区：
文献类型：
--
作者：
Deuchar GA;McLean D;Hadoke PWF;Brownstein DG;Webb DJ;Mullins JJ;Chapman K;Seckl JR;Kotelevtsev YV
盐皮质激素受体 (MR) 激活具有促炎和促动脉粥样硬化的作用。 MR 的拮抗作用可提高动脉粥样硬化性疾病引起的充血性心力衰竭患者的生存率。在动物模型中，MR 的激活会加剧动脉粥样硬化。 11β-羟基类固醇脱氢酶 2 (11β-HSD2) 通过灭活盐皮质激素靶组织中的糖皮质激素，防止糖皮质激素不当激活盐皮质激素受体 (MR)。为了确定糖皮质激素介导的 MR 激活是否会增加动脉粥样硬化斑块的形成，我们生成了 Apoe−/−/11β-HSD2−/− 双敲除 (E/b2) 小鼠。在食物饮食下，E/b2 小鼠在 3 个月大时出现动脉粥样硬化病变，而 Apoe−/− 小鼠则保持无病变。与 6 个月大的 Apoe−/− 小鼠中相似大小的头臂斑块相比，3 个月大的 E/b2 小鼠的头臂斑块显示出巨噬细胞和脂质含量增加，胶原蛋白含量减少。至关重要的是，用 MR 拮抗剂依普利酮治疗 E/b2 小鼠，减少了斑块形成和巨噬细胞浸润，同时增加了胶原蛋白和平滑肌细胞含量，而对收缩压 (SBP) 没有任何影响。相比之下，使用上皮钠通道 (ENaC) 阻断剂阿米洛利降低 E/b2 小鼠的 SBP 产生的动脉粥样硬化保护作用不太明显。与 Apoe−/− 小鼠相比，E/b2 小鼠内皮细胞中血管细胞粘附分子 1 (VCAM-1) 的表达增加。同样，醛固酮会增加小鼠主动脉内皮细胞中 VCAM-1 的表达，只有在 11β-HSD2 抑制剂存在的情况下，皮质酮才能模拟这种效应。因此，11β-HSD2 的缺失会导致显着的动脉粥样硬化形成，这与 E/b2 小鼠内皮细胞中 MR 刺激促炎症过程的激活相关。
Mineralocorticoid receptor (MR) activation is pro inflammatory and pro atherogenic. Antagonism of MR improves survival in humans with congestive heart failure caused by atherosclerotic disease. In animal models, activation of MR exacerbates atherosclerosis. The enzyme 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) prevents inappropriate activation of the mineralocorticoid receptor (MR) from inappropriate activation by glucocorticoids by inactivating glucocorticoids in mineralocorticoid-target tissues. To determine whether glucocorticoid-mediated activation of MR increases atheromatous plaque formation we generated Apoe−/−/11β-HSD2−/− double-knockout (E/b2) mice. On chow diet, E/b2 mice developed atherosclerotic lesions by 3 months of age, while Apoe−/− mice remained lesion-free. Brachiocephalic plaques in 3 month-old E/b2 mice showed increased macrophage and lipid content and reduced collagen content compared to similar sized brachiocephalic plaques in 6 month old Apoe−/− mice. Crucially, treatment of E/b2 mice with eplerenone, an MR antagonist, reduced plaque development and macrophage infiltration while increasing collagen and smooth muscle cell content without any effect on systolic blood pressure (SBP). In contrast, reduction of SBP in E/b2 mice using the epithelial sodium channel (ENaC) blocker amiloride produced a less profound atheroprotective effect. Vascular cell adhesion molecule 1 (VCAM-1) expression was increased in the endothelium of E/b2 mice compared to Apoe−/− mice. Similarly, aldosterone increased VCAM-1 expression in mouse aortic endothelial cells, an effect mimicked by corticosterone only in the presence of an 11β-HSD2 inhibitor. Thus, loss of 11β-HSD2 leads to striking atherogenesis associated with activation of MR stimulating pro-inflammatory processes in the endothelium of E/b2 mice.