title: Eplerenone with valsartan effectively reduces atherosclerotic lesion by attenuation of oxidative stress and inflammation.
abstract: OBJECTIVE
  Angiotensin II contributes to atherogenesis, mainly through oxidative stress and inflammation. Recent data suggest that aldosterone is implicated in some effects of angiotensin II. We hypothesized that aldosterone could directly contribute to oxidative stress and atherosclerotic lesion formation.
  
  
  RESULTS
  Male apolipoprotein E-deficient mice 6 weeks of age were placed on a normal diet or 1.25% high-cholesterol diet. After 6 weeks of the high-cholesterol diet, a marked increase in atherosclerotic lesion formation was observed in the aorta, accompanied by significant elevation of plasma cholesterol level. Production of superoxide anion and expression of NAD(P)H oxidase subunit p47phox, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 in the aorta were increased with the high-cholesterol diet. Eplerenone (1.67 g/kg in high-cholesterol diet) did not affect blood pressure or plasma cholesterol but decreased the atherosclerotic area by nearly 70% (P<0.05), associated with attenuation of oxidative stress and inflammatory response. Valsartan (0.5 mg/kg per day) also decreased the atherosclerotic lesion, whereas coadministration of valsartan and eplerenone further decreased it. Moreover, aldosterone (0.1 micromol/L) enhanced NADPH oxidase activity in cultured vascular smooth muscle cells.
  
  
  CONCLUSIONS
  These results suggest that aldosterone may play a critical role in atherogenesis subsequent to oxidative stress in part independent of angiotensin II-mediated signaling, and that eplerenone could prevent atherosclerosis by attenuating oxidative stress and inflammation.
authors.affiliation: Division of Medical Biochemistry and Cardiovascular Biology, Department of Molecular and Cellular Biology, Ehime University School of Medicine, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Suzuki
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwai
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Akira
authors.initials: A
authors.lastname: Oshita
authors.forename: Toyofumi
authors.initials: T
authors.lastname: Yoshii
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Higaki
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000473:pathology / Q000503:physiopathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004036:Diet, Atherogenic; D004789:Enzyme Activation / Q000187:drug effects; D000077545:Eplerenone; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D002791:Cholesterol, Dietary; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D000068756:Valsartan; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D014633:Valine