Hyperch olesterolemia stimulates angiotensin peptide synthesis and contributes to atherosclerosis through the AT1A receptor

Background-Hypercholesterolemia-induced atherosclerosis is attenuated by either pharmacological antagonism of AT(1) receptors or AT(1A) receptor deficiency. However, the mechanism underlying the pronounced responses to angiotensin II (Ang II) antagonism has not been determined. We hypothesized that hypercholesterolemia stimulates the production of angiotensin peptides to provide a rationale for the profound effect of AT(1A) receptor deficiency on atherogenesis. Methods and Results-Atherosclerotic lesions were analyzed in LDL receptor-deficient mice. Immunocytochemical analysis demonstrated that atherosclerotic lesions contained all the components of the conventional pathway for Ang II synthesis. AT(1A) receptor deficiency caused a marked decrease in atherosclerotic lesion size in both the aortic root and arch of male and female mice, without a discernible effect on composition. AT(1A) receptor deficiency-induced reductions in atherosclerosis were independent of systolic blood pressure and measurements of oxidation and chemoattractants. Aortic AT(2) receptor mRNA expression was not altered in AT(1A) receptor-deficient mice, and AT(2) receptor deficiency had no effect on lesion area or cellular composition. Hypercholesterolemia greatly augmented the systemic renin-angiotensin system, as demonstrated by large increases in plasma concentrations of angiotensinogen and angiotensin peptides (Ang II, III, IV, and 4-8). These increases were ablated in hypercholesterolemic AT(1A) receptor-deficient mice. Conclusions-AT(1A) receptor deficiency had a striking effect in reducing hypercholesterolemia-induced atherosclerosis in LDL receptor-negative mice. Hypercholesterolemia was associated with increased systemic angiotensinogen and angiotensin peptides, which were reduced in AT(1A) receptor-deficient mice. These results demonstrate that hypercholesterolemia-induced stimulation of angiotensin peptide production provides a basis for the marked effect of AT(1A) receptor deficiency in reducing atherosclerosis.