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Updated: Jul 21, 2026
Induction of Atherosclerotic Plaques Through Activation of Mineralocorticoid Receptors in Apolipoprotein E-deficient Mice
Published on: September 26, 2018
Inhibition of diet-induced atherosclerosis and endothelial dysfunction in apolipoprotein E/angiotensin II type 1A
Sven Wassmann1, Thomas Czech, Martin van Eickels
1Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
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.
Insights
Genetic disruption of the Angiotensin II type 1 (AT1) receptor inhibits atherosclerosis development in mice. Blocking AT1 receptor activation prevents vascular oxidative stress and endothelial dysfunction, key factors in atherosclerosis.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Immunology
Background:
- Atherosclerosis pathogenesis involves Angiotensin II type 1 (AT1) receptor activation.
- Understanding AT1 receptor's role is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of AT1 receptor activation in diet-induced atherosclerosis and endothelial dysfunction.
- To determine if AT1 receptor blockade can prevent atherosclerosis development.
Main Methods:
- Generated double-knockout mice (ApoE-/- and AT1-/-).
- Fed mice a high-cholesterol diet and assessed atherosclerotic lesions and vasodilation.
- Measured aortic superoxide radical production and blood pressure.
Main Results:
- ApoE-/- mice developed severe atherosclerosis and endothelial dysfunction.
- Double-knockout mice (ApoE-/-/AT1-/-) showed profoundly inhibited lesion formation and improved endothelial function.
- AT1 receptor blockade, but not general blood pressure reduction, reduced lesions and improved endothelial function.
Conclusions:
- AT1 receptor activation plays a fundamental role in atherogenesis.
- Genetic disruption of the AT1 receptor inhibits vascular oxidative stress, endothelial dysfunction, and atherosclerosis.
- Targeting AT1 receptors offers a promising therapeutic strategy for atherosclerosis.
