title: Role of angiotensin II-regulated apoptosis through distinct AT1 and AT2 receptors in neointimal formation.
abstract: BACKGROUND
  In vitro studies suggest that angiotensin II type 1 and type 2 (AT1 and AT2) receptors exert opposite effects in terms of vasoconstriction, natriuresis, and cell growth, but the role of these receptors in cardiovascular remodeling in vivo is still an enigma. In this study, we tested the hypothesis that AT2 exerts an antiproliferative effect by inducing apoptosis, thereby antagonizing AT1a in vascular remodeling.
  
  
  RESULTS
  Vascular injury was induced by polyethylene cuff placement around the left femoral artery of AT1a-null (AT1aKO), AT2-null (AT2KO), and wild-type mice. Neointimal formation as well as DNA synthesis in vascular smooth muscle cells (VSMC) after vascular injury was exaggerated in AT2KO mice, but they were both suppressed in AT1aKO mice compared with those in wild-type mice. In contrast, the number of apoptotic cells in the injured artery in VSMC was significantly increased in AT1aKO mice but decreased in AT2KO mice. Reverse transcriptase-polymerase chain reaction analysis revealed that the expression of bax mRNA was attenuated in AT2KO mice. On the other hand, the expression of bcl-2 and bcl-x(L) mRNA was enhanced in AT2KO mice but attenuated in AT1aKO mice. Immunohistochemical staining with antibody to the bcl-2 protein family supported these results.
  
  
  CONCLUSIONS
  Our results suggest that AT2 exerts antiproliferative effects and proapoptotic changes in VSMC by counteracting AT1a in the process of neointimal formation after vascular injury.
authors.affiliation: Department of Medical Biochemistry, Ehime University School of Medicine, Ehime, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Suzuki
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwai
authors.forename: Hironori
authors.initials: H
authors.lastname: Nakagami
authors.forename: Lan
authors.initials: L
authors.lastname: Wu
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugaya
authors.forename: Mareomi
authors.initials: M
authors.lastname: Hamada
authors.forename: Kunio
authors.initials: K
authors.lastname: Hiwada
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D002455:Cell Division; D003251:Constriction, Pathologic; D004247:DNA / Q000096:biosynthesis; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology; D014654:Vascular Patency; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D000804:Angiotensin II; D004247:DNA