ABSTRACT
Our interest focused on an open question whether AT-(1-7), nonpeptide receptor agonist: AVE 0991, is able to ameliorate atherosclerosis. We used an apolipoprotein E (apoE) - knockout mice model of atherosclerosis. Experimental groups received the same diet as control, mixed with: AVE 0991 at a dose of 0.58 µmol/kg b.w./day, perindopril at a dose of 0.4 mg/kg b.w./day or with tiorphan at a dose of 2.5 mg/kg b.w./day. A-779 [(D-alanine)-angiotensin (1-7)] was given at a dose of 3.3 mg/kg b.w., 3 times a week i.p. Measured by "en face" method, the percentage of occupied by Sudan IV-stained surfaces were as follows: 14.2±1.9 % in control group, whereas in AVE 0991-treated as well as in perindopril-treated groups percentages were statistically significantly lower. In tiorphan group there was no change comparing to control group, whereas in A-779 group percentage was statistically significantly higher. "Cross-section" of aortic roots revealed also the difference in atherosclerotic lesions. The mean surfaces, occupied by oil red O-stained changes were: 91.213±8.123 µm(2) in control group, while in AVE 0991-treated as well as in perindopril-treated groups lesions were statistically significantly lower. In tiorphan group there was no change; however, in A-779 group lesions were statistically significantly higher. Measured by real time RT-PCR relative p22phox (submit of NADPH oxidase) expression was significantly decreased in AVE 0991-treated mice. As revealed by flow cytometry, the expression of co-stimulatory molecules: CD86, CD80 and CD40 on both dendritic cells (CD11c+) and macrophages (F4/80+) was reduced in AVE 0991-treated group, which correlated with decreased expression of CD69 activation marker on CD4+T cells. In our report we showed the beneficial effect of AVE 0991 on atherogenesis in gene-targeted mice.
Subject(s)
Angiotensin I/agonists , Apolipoproteins E/deficiency , Atherosclerosis/drug therapy , Imidazoles/pharmacology , Peptide Fragments/agonists , Proto-Oncogene Proteins/agonists , Receptors, Angiotensin/agonists , Receptors, G-Protein-Coupled/agonists , Angiotensin I/metabolism , Animals , Antigens, CD/metabolism , Aorta/drug effects , Aorta/metabolism , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Atherosclerosis/genetics , Atherosclerosis/metabolism , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Female , Lipids/blood , Macrophages/drug effects , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Peptide Fragments/metabolism , Perindopril/pharmacology , Proto-Oncogene Mas , Proto-Oncogene Proteins/metabolism , Receptors, Angiotensin/metabolism , Receptors, G-Protein-Coupled/metabolism , Thiorphan/pharmacologyABSTRACT
Doxycycline at subantimicrobial doses inhibits matrix metalloproteinases (MMPs) activity, and is the only MMP inhibitor which is widely available in clinical practice. The aim of the study was to reveal whether non-specific MMPs inhibition by tetracycline could ameliorate development of atherosclerosis in apolipoprotein E (apoE)-knockout mice. Doxycycline (1.5 mg/ kg b.w./day) administered orally attenuated atherogenesis, measured both by "en face" method (10.25±1.7% vs. 15.7±2.0%, p<0.05) and "cross-section" method (66,254±7,468 µm(2) vs. 90,687±8,521 µm(2), p<0.05). In-situ zymography showed decrease of the extent of non-specific gelatinase activity in doxycycline-treated mice This is the first report to date describing the effect of doxycycline on atherogenesis in apoE-targeted mice.
Subject(s)
Apolipoproteins E/deficiency , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Doxycycline/therapeutic use , Animals , Atherosclerosis/genetics , Doxycycline/pharmacology , Female , Matrix Metalloproteinase Inhibitors , Matrix Metalloproteinases/metabolism , Mice , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
Recent evidence shows that the renin-angiotensin system is a crucial player in atherosclerotic processes. It was also proved that Ang II promotes atherogenesis. Angiotensin-(1-7) [Ang-(1-7)] opposites Ang II action. Therefore, we would like to find out whether Ang-(1-7) receptor agonist: AVE 0991, could ameliorate atherosclerosis progression in an experimental model of atherosclerosis: apolipoprotein E (apoE) - knockout mice. AVE 0991 inhibited atherogenesis, measured both by "en face" method (7.63+/-1.6% vs. 14.6+/-2.1%) and "cross-section" method (47 235+/-7 546 microm(2) vs. 91 416+/-8 357 microm(2)). This is the first report showing the effect of AVE 0991 on atherogenesis in gene-targeted mice.
Subject(s)
Apolipoproteins E/genetics , Atherosclerosis/prevention & control , Imidazoles/pharmacology , Proto-Oncogene Proteins/agonists , Receptors, G-Protein-Coupled/agonists , Animals , Atherosclerosis/physiopathology , Disease Models, Animal , Disease Progression , Female , Mice , Mice, Inbred C57BL , Mice, Knockout , Proto-Oncogene MasABSTRACT
Nebivolol is a novel beta1-blocker with a nitric oxide (NO)--potentiating, vasodilatory effect that is unique among beta-blockers. It was already shown that nebivolol ameliorates atherosclerosis in cholesterol-fed rabbits. We, therefore, wanted to investigate whether this is the case in the fine experimental model of atherosclerosis: apolipoprotein E (apoE)-knockout mice. Nebivolol attenuated atherogenesis, measured both by "en face" method (9.23+/-1.8% vs. 14.6+/-2.1%) and "cross-section" method (63125+/-8455 microm(2) vs. 91416+/-8357 m(2)). This is the first report showing the effect of nebivolol on atherogenesis in gene-targeted mice.
