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.

Role of the receptor Mas in macrophage-mediated inflammation in vivo

“…To investigate the role of the Ang-(1-7)/Mas axis on macrophages in vivo, we used two different animal models: EAE, a mouse model for multiple sclerosis (20), and hypercholesterinemic apolipoproteinE knockout (ApoEKO), a mouse model for human atherosclerosis (21).…”

Angiotensin-(1–7) Modulates Renal Vascular Resistance Through Inhibition of p38 Mitogen-Activated Protein Kinase in Apolipoprotein E–Deficient Mice

“…8 Deficiency of the angiotensin II type 1A receptor (AT1aR) in apoE(−/−) mice ameliorates atherosclerosis and endothelial dysfunction, highlighting the importance of the renin-angiotensin system in the pathogen esis of vascular injury. 9,10 Recent studies indicate that p38 mitogenactivated pro tein kinase (MAPK) activation is involved in increased Ang II-dependent vasoconstriction. Inhibition of p38 MAPK has been shown to improve endothelial function and decrease Ang II-dependent vasoconstriction.…”

Deterioration of atherosclerosis in mice lacking angiotensin II type 1A receptor in bone marrow-derived cells

“…Lesion area measurements were performed and the proportion of aortic intimal surface area occupied by red stain was calculated as described previously. 4 …”

“…1 The role of RAS in the pathogenesis of cardiovascular endorgan damages has been well characterized. Interestingly, clinical studies and animal experiments have demonstrated that inhibition of RAS with pharmacological agents such as angiotensin-converting enzyme inhibitors and AT1 receptor blockers (ARBs), as well as genetic disruption of RAS signaling components, diminishes end-organ damage, particularly atherosclerosis [2][3][4] and kidney injury. 5,6 The mechanisms underlying these effects have been studied predominately in cells derived from a variety of organs expressing AT1 receptors, such as blood vessel, heart and kidney cells.…”