Abstract
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 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.
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.
MeSH terms
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Aldosterone / pharmacology*
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Aldosterone / physiology
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Aldosterone / toxicity
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Angiotensin II / physiology*
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Angiotensin II Type 1 Receptor Blockers
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Angiotensin-Converting Enzyme Inhibitors / pharmacology
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Angiotensin-Converting Enzyme Inhibitors / therapeutic use
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Animals
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Aortic Diseases / chemically induced
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Aortic Diseases / metabolism
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Aortic Diseases / pathology
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Apolipoproteins E / deficiency
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Apolipoproteins E / genetics
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Arteriosclerosis / chemically induced*
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Arteriosclerosis / metabolism
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Arteriosclerosis / pathology
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Arteriosclerosis / prevention & control
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Cell Line / drug effects
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Cell Line / metabolism
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Enzyme Induction / drug effects
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Eplerenone
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Hormone Antagonists / pharmacology
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Hormone Antagonists / therapeutic use
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Humans
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Lipid Peroxidation / drug effects
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Lipoproteins, LDL / metabolism
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Losartan / pharmacology
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Losartan / therapeutic use
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Macrophages, Peritoneal / drug effects*
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Macrophages, Peritoneal / enzymology
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Mineralocorticoid Receptor Antagonists
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NADPH Oxidases / metabolism*
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Oxidative Stress / drug effects
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Peptidyl-Dipeptidase A / biosynthesis
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Peptidyl-Dipeptidase A / genetics
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Peptidyl-Dipeptidase A / physiology*
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Phosphoproteins / metabolism
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Protein Transport / drug effects
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RNA, Messenger / biosynthesis
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Ramipril / pharmacology
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Ramipril / therapeutic use
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Receptor, Angiotensin, Type 1 / physiology*
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Receptors, Mineralocorticoid / physiology*
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Spironolactone / analogs & derivatives*
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Spironolactone / pharmacology
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Spironolactone / therapeutic use
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Superoxides / metabolism
Substances
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Angiotensin II Type 1 Receptor Blockers
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Angiotensin-Converting Enzyme Inhibitors
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Apolipoproteins E
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Hormone Antagonists
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Lipoproteins, LDL
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Membrane Proteins
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Mineralocorticoid Receptor Antagonists
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Phosphoproteins
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RNA, Messenger
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Receptor, Angiotensin, Type 1
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Receptors, Mineralocorticoid
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oxidized low density lipoprotein
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Superoxides
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Angiotensin II
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Spironolactone
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Aldosterone
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Eplerenone
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NADPH Oxidases
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neutrophil cytosolic factor 1
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Peptidyl-Dipeptidase A
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Losartan
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Ramipril