ABSTRACT
Angiotensin converting enzyme (ACE) inhibitors prevent a wide variety of key events underlying atherogenesis. Whether these actions depend solely on reduction of angiotensin II (Ang II) generation is still to be determined. This study was undertaken to determine whether enalapril, an ACE inhibitor, prevents atherosclerosis and vascular inflammation induced by Ang II in apolipoprotein E-deficient (apoE-KO) mice. Subcutaneous infusion of Ang II (1.44 mg/(kg day)) for 4 weeks increased blood pressure and accelerated atherosclerosis development in the carotid arteries. The expression of the endothelial adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as well as the chemokines monocyte chemotactic protein-1 (MCP-1) and macrophage-colony stimulating factor (M-CSF) was up-regulated in the aortas of Ang II-treated mice. Enalapril co-treatment (25 mg/(kg day), in drinking water) prevented the development of atherosclerosis without affecting blood pressure or circulating cholesterol. In addition to preventing the Ang II-induced over-expression of adhesion molecules and chemokines in the aorta, enalapril up-regulated the expression of peroxisome proliferator-activated receptors (PPARs)-alpha and -gamma, potential anti-inflammatory transcription factors. In the aortic arch, a lesion-prone site, the co-treatment with enalapril reduced the percentage of arterial wall occupied by macrophages and foam cells, medial sclerosis and elastin reduplication. Together, these data suggest an important role for Ang II-independent mechanisms in the antiatherogenic and anti-inflammatory effects of ACE inhibitors.
Subject(s)
Angiotensin II , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Arteriosclerosis/chemically induced , Arteriosclerosis/pathology , Enalapril/pharmacology , Vasculitis/chemically induced , Vasculitis/pathology , Animals , Aorta/metabolism , Aortic Aneurysm/chemically induced , Aortic Aneurysm/prevention & control , Apolipoproteins E/deficiency , Cell Adhesion Molecules/genetics , Chemokines/metabolism , Endothelium/metabolism , Gene Expression/drug effects , Male , Mice , Mice, Knockout , PPAR alpha/genetics , PPAR gamma/genetics , RNA, Messenger/metabolism , Up-RegulationABSTRACT
OBJECTIVE: Angiotensin II (Ang II) promotes vascular inflammation, accelerates atherosclerosis, and induces abdominal aortic aneurysm (AAA). These changes were associated with activation of nuclear factor (NF)-kappaB-mediated induction of proinflammatory genes. The incidence of AAA in this model was higher in male than in female mice, and the vascular effects of estrogen may be associated with anti-inflammatory actions. The present study was undertaken to test the hypothesis that estrogen can attenuate Ang II-induced AAA in apolipoprotein E-deficient mice via its anti-inflammatory mechanism. METHODS AND RESULTS: Infusion of Ang II (1.44 mg/kg per d for 1 month) induced AAA in 90% of the animals (n=20) with an expansion of the suprarenal aorta (diameter 1.9+/-0.14 mm versus <1 mm in normal mice). In mice treated with 17beta-estradiol (E2, 0.25-mg subcutaneous pellets), Ang II induced AAA only in 42% of the animals (n=19) with a significant reduction of average diameters of the suprarenal aorta (1.5+/-0.14 mm). E2 also decreased the expressions of intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, E-selectin, monocyte chemotactic protein-1, and macrophage-colony stimulating factor in the aorta. CONCLUSIONS: These data suggest that attenuation of AAA by E2 is associated with inhibition of proinflammatory gene expression.
