title: Deletion of angiotensin II type 2 receptor exaggerated atherosclerosis in apolipoprotein E-null mice.
abstract: BACKGROUND
  The role of angiotensin II (Ang II) type 2 (AT2) receptor in atherosclerosis was explored with the use of AT2 receptor/apolipoprotein E (ApoE)-double-knockout (AT2/ApoE-DKO) mice, with a focus on oxidative stress.
  
  
  RESULTS
  After treatment with a high-cholesterol diet (1.25% cholesterol) for 10 weeks, ApoE-knockout (KO) mice developed atherosclerotic lesions in the aorta. In AT2/ApoE-DKO mice receiving a high-cholesterol diet, the atherosclerotic changes were further exaggerated, without significant changes in plasma cholesterol level and blood pressure. In the atherosclerotic lesion, an increase in superoxide production, NADPH oxidase activity, and expression of p47phox was observed. These changes were also greater in AT2/ApoE-DKO mice. An Ang II type 1 (AT1) receptor blocker, valsartan, inhibited atherosclerotic lesion formation, superoxide production, NADPH oxidase activity, and p47phox expression; these inhibitory effects were significantly weaker in AT2/ApoE-KO mice. We further examined the signaling mechanism of the AT2 receptor-mediated antioxidative effect in cultured fetal vascular smooth muscle cells. NADPH oxidase activity and phosphorylation and translocation of p47phox induced by Ang II were inhibited by valsartan but enhanced by an AT2 receptor blocker, PD123319.
  
  
  CONCLUSIONS
  These results suggest that AT2 receptor stimulation attenuates atherosclerosis through inhibition of oxidative stress and that the antiatherosclerotic effect of valsartan could be at least partly due to AT2 receptor stimulation by unbound Ang II.
authors.affiliation: Division of Medical Biochemistry and Cardiovascular Biology, Department of Molecular and Cellular Biology, Ehime University School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwai
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shiuchi
authors.forename: Jun
authors.initials: J
authors.lastname: Suzuki
authors.forename: Ayumi
authors.initials: A
authors.lastname: Ide
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuda
authors.forename: Midori
authors.initials: M
authors.lastname: Okumura
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Min
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D002478:Cells, Cultured; D017353:Gene Deletion; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D010750:Phosphoproteins; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000187:drug effects / Q000235:genetics*; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D001057:Apolipoproteins E; D007093:Imidazoles; D010750:Phosphoproteins; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; D000068756:Valsartan; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D051057:Proto-Oncogene Proteins c-akt; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; D014633:Valine