Inhibition of diet-induced atherosclerosis and endothelial dysfunction in apolipoprotein E/angiotensin II type 1A receptor double-knockout mice.

Abstract

BACKGROUND:

Angiotensin II type 1 (AT1) receptor activation is potentially involved in the multifactorial pathogenesis of atherosclerosis.

METHODS AND 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.

• Authors: Sven Wassmann, Thomas Czech, Martin van Eickels, Ingrid Fleming, Michael Böhm, Georg Nickenig
• Journal: Circulation (Circulation) Vol. 110 Issue 19 Pg. 3062-7 (Nov 09 2004) ISSN: 1524-4539 [Electronic] United States
• PMID: 15277329 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Apolipoproteins E
• Biphenyl Compounds
• Cholesterol, Dietary
• Receptor, Angiotensin, Type 1
• Tetrazoles
• Superoxides
• Hydralazine
• Renin
• Irbesartan

Topics

• Angiotensin II Type 1 Receptor Blockers (therapeutic use)
• Animals
• Aortic Diseases (etiology, genetics, physiopathology, prevention & control)
• Apolipoproteins E (deficiency, genetics, physiology)
• Arteriosclerosis (drug therapy, etiology, genetics, physiopathology, prevention & control)
• Biphenyl Compounds (therapeutic use)
• Cholesterol, Dietary (toxicity)
• Diet, Atherogenic
• Genetic Predisposition to Disease
• Hemodynamics
• Hydralazine (therapeutic use)
• Hyperlipoproteinemia Type II (complications, genetics)
• Irbesartan
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Receptor, Angiotensin, Type 1 (deficiency, genetics, physiology)
• Renin (blood)
• Superoxides (metabolism)
• Tetrazoles (therapeutic use)
• Vasoconstriction (drug effects)