Inhibition of renin-angiotensin system attenuates periadventitial inflammation and reduces atherosclerotic lesion formation.
Recent evidence indicates that renin-angiotensin system (RAS) plays an important role in the pathogenesis of atherosclerosis. It was reported that inhibition of RAS with angiotensin II type 1 receptor blockers (ARBs) or angiotensin converting enzyme inhibitors (ACEIs) is effective in prevention of atherosclerosis. Here, we investigated the effects of an ARB or/and an ACEI on atherosclerosis development and periadventitial inflammation in apolipoprotein E (ApoE)-deficient mice. RT-PCR revealed that major RAS components were expressed in periaortic tissue. Ang II infusion significantly increased accumulation of bone marrow derived cells into both neointima (p<0.05) and periaortic tissue (p<0.01). Male ApoE- deficient mice were treated with either vehicle, TA606A (10mg/kg/day, ARB), imidapril (3mg/kg/day, ACEI) or TA606A plus imidapril (TA606A 10mg/kg/day+imidapril 3mg/kg/day, ARB+ACEI) for 24 weeks starting at 12 weeks of age. ARB, ACEI, and ARB+ACEI significantly reduced atherosclerotic lesion formation in aorta compared with vehicle (p<0.05), with reduced expression of monocyte chemoattractant protein-1 in periaortic tissues (p<0.01). Neither blood pressure nor heart rate was changed by the treatments at these lower doses. Imidapril significantly reduced lipid deposition in atheroma and plasminogen activator inhibitor-1 expression in periadventitial tissue (p<0.05, respectively). Imidapril and combination therapy significantly attenuated macrophage infiltration into the atherosclerotic plaque (p<0.05, respectively). All treatments reduced macrophage accumulation in the periadventitial tissue 12 weeks after treatment (p<0.05, respectively). These results suggest that inhibition of renin-angiotensin system attenuates periadventitial inflammation and reduces atherosclerotic lesion formation.
Fukuda
Daiju
D
Department of Cardiovascular Medicine, University of Tokyo, Graduate School of Medicine, Tokyo 113-8655, Japan.
Enomoto
Soichiro
S
Nagai
Ryozo
R
Sata
Masataka
M
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000503:physiopathology / Q000517:prevention & control; D018932:Chemokine CCL2 / Q000235:genetics; D003238:Connective Tissue / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001057:Apolipoproteins E; D018932:Chemokine CCL2; D007093:Imidazoles; D048289:Imidazolidines; D011725:Pyridines; C112300:TA 606; D013777:Tetrazoles; C065166:imidapril