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

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.