Aldosterone administration to mice stimulates macrophage NADPH oxidase and increases atherosclerosis development - A possible role for angiotensin-converting enzyme and the receptors for angiotensin II and aldosterone
Aldosterone administration to mice stimulates macrophage NADPH oxidase and increases atherosclerosis development - A possible role for angiotensin-converting enzyme and the receptors for angiotensin II and aldosterone
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DOI：
10.1161/01.cir.0000127949.05756.9d
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发表时间：
2004-05-11
期刊：
影响因子：
37.8
通讯作者：
Aviram, M
中科院分区：
文献类型：
--
作者：
Keidar, S;Kaplan, M;Aviram, M
背景：肾素-血管紧张素-醛固酮系统参与动脉粥样硬化的发病机制，部分原因是其促氧化特性。我们质疑的作用和机制的醛固酮给药的载脂蛋白E-缺陷（E-0）小鼠对他们的巨噬细胞和主动脉氧化状态和药理学试剂的能力，以阻止这种影响。小鼠（-1）。d（-1））单独或与依普利酮（200 mg . kg（-1）。d（-1）），雷米普利5 mg . kg（-1）。d（-1））或氯沙坦（25 mg . kg（-1）。d（-1））。检测小鼠主动脉粥样硬化病变面积、巨噬细胞及主动脉氧化状态。醛固酮给药使小鼠动脉粥样硬化病变面积增加32%。小鼠腹腔巨噬细胞和主动脉段醛固酮治疗的小鼠表现出增加超氧阴离子形成高达155%和69%，分别，这种效果可能是由NADPH氧化酶激活介导的，因为增加其胞质组分p47（phox）的转移到巨噬细胞质膜观察。与对照细胞相比，醛固酮（10 μ mol/L）体外孵育的THP-1巨噬细胞释放超氧阴离子的能力提高了110%，氧化LDL的能力提高了74%。醛固酮给药增强小鼠腹腔巨噬细胞ACE活性和mRNA表达的2.3倍和2.4倍，分别。只有cotreatment的依普利酮与雷米普利或losartan完全阻断了氧化作用的aldosterone. Conclusions-醛固酮给药E-0小鼠增加巨噬细胞氧化应激和动脉粥样硬化病变的发展。阻断盐皮质激素受体和抑制组织ACE和/或血管紧张素受体-1可降低醛固酮的有害促氧化和促动脉粥样硬化作用。
Background-The renin-angiotensin-aldosterone system is involved in the pathogenesis of atherosclerosis, partially because of its pro-oxidative properties. We questioned the effect and mechanisms of action of administration of aldosterone to apolipoprotein E-deficient (E-0) mice on their macrophages and aorta oxidative status and the ability of pharmacological agents to block this effect.Methods and Results-Aldosterone (0.2 to 6 mug . mouse(-1) . d(-1)) was administered to E-0 mice alone or in combination with eplerenone (200 mg . kg(-1) . d(-1)), ramipril (5 mg . kg(-1) . d(-1)), or losartan ( 25 mg . kg(-1) . d(-1)). Mouse aortic atherosclerotic lesion area and macrophage and aortic oxidative status were evaluated. Aldosterone administration enhanced the mouse atherosclerotic lesion area by 32%. Mouse peritoneal macrophages and aortic segments from aldosterone-treated mice exhibited increased superoxide anion formation by up to 155% and 69%, respectively, and this effect was probably mediated by NADPH oxidase activation, because increased translocation of its cytosolic component p47(phox) to the macrophage plasma membrane was observed. THP-1 macrophages incubated in vitro with aldosterone (10 mumol/L) exhibited a higher capacity to release superoxide ions by 110% and increased ability to oxidize LDL by 74% compared with control cells. Aldosterone administration enhanced mouse peritoneal macrophage ACE activity and mRNA expression by 2.3-fold and 2.4-fold, respectively. Only cotreatment of eplerenone with ramipril or losartan completely blocked the oxidative effects of aldosterone.Conclusions-Aldosterone administration to E-0 mice increased macrophage oxidative stress and atherosclerotic lesion development. Blocking of the mineralocorticoid receptor and inhibition of tissue ACE and/or the angiotensin receptor-1 reduced aldosterone deleterious pro-oxidative and proatherogenic effects.