eplerenone and Aortic-Diseases

The beneficial effects of eplerenone, a specific mineralocorticoid receptor blocker, were previously demonstrated in early atherosclerosis (ATS). The aim of the present study was to evaluate the effect of eplerenone in advanced versus early ATS. Apolipoprotein E knockout mice aged 16 or 32 weeks were randomly divided into eplerenone (100 mg·kg·d) or vehicle treatment for 14 weeks. Eplerenone reduced atherosclerotic lesion size by 51% only in early ATS. In peritoneal macrophages obtained from these mice, eplerenone reduced messenger RNA expression of pro-inflammatory markers, interleukin 6, tumor necrosis factor α, monocyte chemotactic protein 1, and increased anti-inflammatory marker arginase 1 to a greater extent in early compared with advanced ATS. These changes correspond to macrophage polarization toward alternative inflammatory phenotype. Messenger RNA expression of the mineralocorticoid receptor and aldosterone synthase were also reduced by eplerenone to a greater extent in early ATS, and these might increase the sensitivity of macrophages to mineralocorticoid blockade in early ATS. The results of the present study point to the benefits of early initiation of treatment with eplerenone in reducing experimental ATS.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Cytochrome P-450 CYP11B2; Cytokines; Disease Models, Animal; Disease Progression; Eplerenone; Inflammation Mediators; Lipids; Macrophages, Peritoneal; Male; Mice; Mice, Knockout; Mineralocorticoid Receptor Antagonists; Plaque, Atherosclerotic; Receptors, Mineralocorticoid; RNA, Messenger; Spironolactone

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.. Aldosterone (0.2 to 6 microg. mouse(-1) x d(-1)) was administered to E(0) mice alone or in combination with eplerenone (200 mg x kg(-1) x d(-1)), ramipril (5 mg x kg(-1) x d(-1)), or losartan (25 mg x kg(-1) x 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 micromol/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.. 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.

Topics: Aldosterone; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Aortic Diseases; Apolipoproteins E; Arteriosclerosis; Cell Line; Enzyme Induction; Eplerenone; Hormone Antagonists; Humans; Lipid Peroxidation; Lipoproteins, LDL; Losartan; Macrophages, Peritoneal; Membrane Proteins; Mice; Mice, Knockout; Mineralocorticoid Receptor Antagonists; NADPH Oxidases; Oxidative Stress; Peptidyl-Dipeptidase A; Phosphoproteins; Protein Transport; Ramipril; Receptor, Angiotensin, Type 1; Receptors, Mineralocorticoid; RNA, Messenger; Spironolactone; Superoxides