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: Kousei Ohshima, Masaki Mogi, Hirotomo Nakaoka, Jun Iwanami, Li-Juan Min, Harumi Kanno, Kana Tsukuda, Toshiyuki Chisaka, Hui-Yu Bai, Xiao-Li Wang, Akiyoshi Ogimoto, Jitsuo Higaki, Masatsugu Horiuchi
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 63 Issue 3 Pg. e53-9 (Mar 2014) ISSN: 1524-4563 [Electronic] United States
• PMID: 24379178 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Peptide Fragments
• Receptor, Angiotensin, Type 2
• Vasodilator Agents
• RNA
• Angiotensin I
• Peptidyl-Dipeptidase A
• Ace2 protein, mouse
• Angiotensin-Converting Enzyme 2
• angiotensin I (1-7)

Topics

• Angiotensin I (pharmacology)
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Angiotensin-Converting Enzyme 2
• Animals
• Disease Models, Animal
• Gene Expression Regulation
• Immunohistochemistry
• Mice
• Mice, Inbred C57BL
• Oxidative Stress
• Peptide Fragments (pharmacology)
• Peptidyl-Dipeptidase A (genetics, metabolism)
• RNA (genetics, metabolism)
• Real-Time Polymerase Chain Reaction
• Receptor, Angiotensin, Type 2 (genetics, metabolism)
• Vascular Resistance
• Vasodilator Agents (pharmacology)