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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

2013; Lippincott Williams & Wilkins; Volume: 63; Issue: 3 Linguagem: Inglês

10.1161/hypertensionaha.113.02426

1524-4563

Kousei Ohshima, Masaki Mogi, Hirotomo Nakaoka, Jun Iwanami, Li‐Juan Min, Harumi Kan‐no, Kana Tsukuda, Toshiyuki Chisaka, Hui‐Yu Bai, Xiaoli Wang, Akiyoshi Ogimoto, Jitsuo Higaki, Masatsugu Horiuchi,

Hormonal Regulation and Hypertension

Cross talk between the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/Ang II type 1 (AT 1 ) 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 (AT 2 ) 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)/AT 2 receptor axis are involved in the inhibitory effects of AT 1 receptor blockers on vascular remodeling. Wild-type, Mas-knockout, and AT 2 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 AT 1 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 AT 2 receptor mRNA but did not affect AT 1 receptor mRNA or the decrease in Mas mRNA. The inhibitory effect of Ang-(1–7) on neointimal formation was less marked in AT 2 receptor knockout mice compared with wild-type mice. These results suggest that blockade of the AT 1 receptor by azilsartan could enhance the activities of the ACE2/Ang-(1–7)/Mas axis and ACE2/Ang-(1–7)/AT 2 receptor axis, thereby inhibiting neointimal formation.