title: Hypercholesterolemia stimulates angiotensin peptide synthesis and contributes to atherosclerosis through the AT1A receptor.
abstract: BACKGROUND
  Hypercholesterolemia-induced atherosclerosis is attenuated by either pharmacological antagonism of AT1 receptors or AT1A 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 AT1A receptor deficiency on atherogenesis.
  
  
  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. AT1A 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. AT1A receptor deficiency-induced reductions in atherosclerosis were independent of systolic blood pressure and measurements of oxidation and chemoattractants. Aortic AT2 receptor mRNA expression was not altered in AT1A receptor-deficient mice, and AT2 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 AT1A receptor-deficient mice.
  
  
  CONCLUSIONS
  AT1A 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 AT1A receptor-deficient mice. These results demonstrate that hypercholesterolemia-induced stimulation of angiotensin peptide production provides a basis for the marked effect of AT1A receptor deficiency in reducing atherosclerosis.
authors.affiliation: Division of Cardiovascular Medicine, Wethington Building, Room 521, University of Kentucky, Lexington, KY 40536-0200, USA. alan.daugherty@uky.edu
authors.forename: Alan
authors.initials: A
authors.lastname: Daugherty
authors.forename: Debra L
authors.initials: DL
authors.lastname: Rateri
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Tadashi
authors.initials: T
authors.lastname: Inagami
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cassis
mesh_terms: D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000502:physiology*; D000805:Angiotensin III / Q000097:blood; D000808:Angiotensinogen / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001018:Aortic Diseases / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D001161:Arteriosclerosis / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D018932:Chemokine CCL2 / Q000097:blood; D002645:Chickens / Q000276:immunology; D004036:Diet, Atherogenic; D005260:Female; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D007703:Peptidyl-Dipeptidase A / Q000032:analysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012084:Renin-Angiotensin System / Q000502:physiology
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011973:Receptors, LDL; D000808:Angiotensinogen; D000804:Angiotensin II; D000805:Angiotensin III; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D007703:Peptidyl-Dipeptidase A