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
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
复制标题
DOI：
10.1161/hypertensionaha.113.02426
复制
发表时间：
2014-03-01
期刊：
影响因子：
8.3
通讯作者：
Horiuchi, Masatsugu
中科院分区：
文献类型：
--
作者：
Ohshima, Kousei;Mogi, Masaki;Horiuchi, Masatsugu
血管紧张素转换酶(ACE)/血管紧张素II(Ang II)/Ang II 1型(AT1)受体轴和ACE2/Ang-(1-7)/mAs轴之间的相互作用在心血管重构的发病机制中起着重要作用。此外，Ang-(1-7)可能刺激血管紧张素Ⅱ受体2(AT2)是一种新的途径。因此，我们探讨了ACE2/Ang-(1-7)/mAs轴和Ang-(1-7)/AT2受体轴是否参与了AT1受体阻滞剂对血管重构的抑制作用。本研究使用野生型、Mas基因敲除和AT2受体基因敲除小鼠。小鼠股动脉周围放置聚乙烯袖带造成血管损伤。一些小鼠接受AT1受体阻滞剂阿奇沙坦或Ang-(1-7)的治疗。与野生型小鼠相比，Mas基因敲除小鼠在放置袖带2周后的新生内膜形成更明显。阿齐沙坦或血管紧张素-(1-7)治疗可减少损伤动脉新生内膜面积、血管平滑肌细胞增殖、单核细胞趋化蛋白-1、肿瘤坏死因子-α和白介素1β的表达水平，以及超氧阴离子的产生，但在Mas基因敲除小鼠，这些抑制作用不明显。给予阿奇沙坦或Ang-(1-7)可减轻血管紧张素转换酶2(ACE2)mRNA的下降和AT2受体mRNA的升高，但不影响AT1受体和Mas mRNA的下降。在AT2受体基因敲除小鼠中，Ang-(1-7)对新生内膜形成的抑制作用不如野生型小鼠明显。提示阿奇沙坦阻断AT1受体可增强ACE2/Ang-(1-7)/mAs轴和ACE2/Ang-(1-7)/AT2受体轴的活性，从而抑制新生内膜的形成。
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)/AT2receptor axis are involved in the inhibitory effects of AT1receptor blockers on vascular remodeling. Wild-type, Mas-knockout, and AT2receptor 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 AT1receptor 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 AT2receptor mRNA but did not affect AT1receptor mRNA or the decrease in Mas mRNA. The inhibitory effect of Ang-(1–7) on neointimal formation was less marked in AT2receptor knockout mice compared with wild-type mice. These results suggest that blockade of the AT1receptor by azilsartan could enhance the activities of the ACE2/Ang-(1–7)/Mas axis and ACE2/Ang-(1–7)/AT2receptor axis, thereby inhibiting neointimal formation.