on May 3, 2004
Published online before print May 3, 2004, doi: 10.1161/01.CIR.0000127949.05756.9D
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Submitted on May 22, 2003
From the Lipid Research Laboratory, Technion Faculty of Medicine, the Rappaport Family Institute for Research in Medical Sciences and Rambam Medical Center, Haifa, Israel. * To whom correspondence should be addressed. E-mail: skeidar{at}rambam.health.gov.il.
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.
Revised on October 28, 2003
Accepted on January 30, 2004
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
Shlomo Keidar MD*,
Key words: aldosterone • atherosclerosis • macrophages • angiotensin • angiotensin-converting enzyme
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