title: Possible role of angiotensin-converting enzyme 2 and activation of angiotensin II type 2 receptor by angiotensin-(1-7) in improvement of vascular remodeling by angiotensin II type 1 receptor blockade.
abstract: Cross talk between the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/Ang II type 1 (AT1) receptor axis and the ACE2/Ang-(1-7)/Mas axis plays a role in the pathogenesis of cardiovascular remodeling. Furthermore, possible stimulation of the Ang II type 2 (AT2) receptor by Ang-(1-7) has been highlighted as a new pathway. Therefore, we examined the possibility of whether the ACE2/Ang-(1-7)/Mas axis and Ang-(1-7)/AT2 receptor axis are involved in the inhibitory effects of AT1 receptor blockers on vascular remodeling. Wild-type, Mas-knockout, and AT2 receptor knockout mice were used in this study. Vascular injury was induced by polyethylene-cuff placement around the mouse femoral artery. Some mice were treated with azilsartan, an AT1 receptor blocker, or Ang-(1-7). Neointimal formation 2 weeks after cuff placement was more marked in Mas-knockout mice compared with wild-type mice. Treatment with azilsartan or Ang-(1-7) attenuated neointimal area, vascular smooth muscle cell proliferation, increases in the mRNA levels of monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-1β, and superoxide anion production in the injured artery; however, these inhibitory effects of azilsartan and Ang-(1-7) were less marked in Mas-knockout mice. Administration of azilsartan or Ang-(1-7) attenuated the decrease in ACE2 mRNA and increased AT2 receptor mRNA but did not affect AT1 receptor mRNA or the decrease in Mas mRNA. The inhibitory effect of Ang-(1-7) on neointimal formation was less marked in AT2 receptor knockout mice compared with wild-type mice. These results suggest that blockade of the AT1 receptor by azilsartan could enhance the activities of the ACE2/Ang-(1-7)/Mas axis and ACE2/Ang-(1-7)/AT2 receptor axis, thereby inhibiting neointimal formation.
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan. horiuchi@m.ehime-u.ac.jp.
authors.forename: Kousei
authors.initials: K
authors.lastname: Ohshima
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Nakaoka
authors.forename: Jun
authors.initials: J
authors.lastname: Iwanami
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Min
authors.forename: Harumi
authors.initials: H
authors.lastname: Kanno
authors.forename: Kana
authors.initials: K
authors.lastname: Tsukuda
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Chisaka
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Bai
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Wang
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Ogimoto
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Higaki
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics* / Q000378:metabolism; D014655:Vascular Resistance; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D010446:Peptide Fragments; D044139:Receptor, Angiotensin, Type 2; D014665:Vasodilator Agents; D012313:RNA; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)
keywords: angiotensin; angiotensin-converting enzyme 2; inflammation; oxidative stress; receptors; remodeling