Role of ACE2 in the Cardioprotective Effects of Angiotensin II Type 2 Receptors

Abstract

Blockade of angiotensin II (Ang II) type 1 receptors with angiotensin receptor blockers (ARBs) activates the Ang II type 2 receptors (AT2) and also increases angiotensin‐converting enzyme 2 (ACE2) expression and Ang 1–7 levels. However, it is not known whether activation of AT2 and ACE2 are synergistically associated to exert cardioprotection. We hypothesize that activation of AT2 increases the expression and activity of ACE2, leading to cardioprotection. Transgenic mice with cardiac overexpression of AT2 (Tg‐AT2) were subjected to myocardial infarction (MI) for 12 weeks. We found that Tg‐AT2 mice had cardiac ACE2 protein expression 2.36±0.07‐fold higher than the wild‐type (WT) controls, associated with better preserved cardiac function compared with WT controls (ejection fraction: 41.6±2.3% vs 27.6±1.8%). In AT2‐stimulated coronary artery endothelial cells, ACE2 protein expression was increased by 1.79±0.04‐fold and ACE2 activity was enhanced from 0.61± 0.05 (basal) to 0.95±0.03 pg/μl/h/μg protein. These effects were blunted by AT2 antagonist. Furthermore, activation of AT2 increased cGMP by 1.71±0.12‐fold, which was diminished by Mas receptors antagonist. AT2 activation also increased Ang 1–7 from 0.1±0.05 (basal) to 15.6±0.5 (pg/ml/μg protein) and this effect was diminished by the AT2 antagonist. Our data suggest that the cardioprotective effects of AT2 is in part mediated via activation of ACE2, enhancing the release of Ang 1–7 and leading to cardioprotection.