Published online before print May 3, 2004, doi: 10.1161/01.CIR.0000127949.05756.9D
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(Circulation. 2004;109:2213-2220.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
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
From the Lipid Research Laboratory, Technion Faculty of Medicine, the Rappaport Family Institute for Research in Medical Sciences and Rambam Medical Center, Haifa, Israel.
Correspondence to Prof Shlomo Keidar, Head of Internal Medicine Department-A, Rambam Medical Center, Haifa, 31096, Israel. E-mail skeidar{at}rambam.health.gov.il
Received May 22, 2003; de novo received October 28, 2003; accepted January 30, 2004.
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 (E0) 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 µg · mouse–1 · d–1) was administered to E0 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 p47phox to the macrophage plasma membrane was observed. THP-1 macrophages incubated in vitro with aldosterone (10 µmol/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 E0 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.
Key Words: aldosterone • atherosclerosis • macrophages • angiotensin • angiotensin-converting enzyme
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