Inhibition of diet-induced atherosclerosis and endothelial dysfunction in apolipoprotein E/angiotensin II type 1A receptor double-knockout mice.
BACKGROUND
Angiotensin II type 1 (AT1) receptor activation is potentially involved in the multifactorial pathogenesis of atherosclerosis.


RESULTS
Apolipoprotein E-deficient (ApoE-/-) mice were crossed with AT1A receptor-deficient (AT1-/-) mice to obtain homozygous double-knockout animals (ApoE-/--AT1-/- mice). Wild-type (C57BL/6J), ApoE-/-, AT1-/-, and ApoE-/--AT1-/- mice were fed a high-cholesterol diet for 7 weeks. In contrast to wild-type and AT1-/- mice, this treatment led to severe atherosclerotic lesion formation in the aortic sinus and the aorta (oil red O staining) and to an impaired endothelium-dependent vasodilation (organ chamber experiments with isolated aortic segments) in ApoE-/- mice. In the age-matched ApoE-/--AT1-/- littermates, development of diet-induced endothelial dysfunction and atherosclerotic lesion formation was profoundly inhibited. Concomitantly, aortic release of superoxide radicals was increased 2-fold in ApoE-/- mice compared with wild-type animals, whereas aortic superoxide production was normalized in ApoE-/--AT1-/- mice (L-012 chemiluminescence). There were no significant differences in plasma cholesterol levels between ApoE-/- and ApoE-/--AT1-/- animals. Systolic blood pressure was significantly lower in ApoE-/--AT1-/- animals than in ApoE-/- mice (tail-cuff measurements). Oral treatment of ApoE-/- mice with either hydralazine or irbesartan reduced systolic blood pressure to the same level; however, only AT1 receptor antagonist treatment reduced atherosclerotic lesion formation and improved endothelial function.


CONCLUSIONS
Genetic disruption of the AT1A receptor leads to inhibition of vascular oxidative stress, endothelial dysfunction, and atherosclerotic lesion formation in ApoE-/- mice irrespective of blood pressure and plasma cholesterol levels. These results indicate a fundamental role of AT1 receptor activation in atherogenesis.
Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
Sven
S
Wassmann
Thomas
T
Czech
Martin
M
van Eickels
Ingrid
I
Fleming
Michael
M
Böhm
Georg
G
Nickenig
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D001018:Aortic Diseases / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D001161:Arteriosclerosis / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D001713:Biphenyl Compounds / Q000627:therapeutic use; D002791:Cholesterol, Dietary / Q000633:toxicity; D004036:Diet, Atherogenic; D020022:Genetic Predisposition to Disease; D006439:Hemodynamics; D006830:Hydralazine / Q000627:therapeutic use; D006938:Hyperlipoproteinemia Type II / Q000150:complications* / Q000235:genetics; D000077405:Irbesartan; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D012083:Renin / Q000097:blood; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000627:therapeutic use; D014661:Vasoconstriction / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D001713:Biphenyl Compounds; D002791:Cholesterol, Dietary; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D013481:Superoxides; D006830:Hydralazine; D012083:Renin; D000077405:Irbesartan