Abstract 14355: Angiotensin II Type 2 Receptors Contribute to the Cardioprotective and Anti-Inflammatory Effects of ARBs Post-Myocardial Infarction
Angiotensin II acts mainly on two types of receptors: AT1 and AT2. Most effects of angiotensin II are mediated by AT1, whereas the role of AT2 remains unclear. We and others have demonstrated that activation of AT2 plays an important role in the cardioprotective effects of AT1 receptor blockers (ARBs). Recently, AT2 has been reported to exhibit an anti-inflammatory action in vascular and renal injuries. We hypothesized that the beneficial cardiac effects of ARBs are partly due to AT2-mediated anti-inflammatory mechanisms. Male C57BL/6J mice were subjected to sham myocardial infarction (MI) or MI by ligating the left anterior descending coronary artery and treated with 1) vehicle, 2) ARB (valsartan, 50 mg/kg/day in drinking water) or 3) ARB + AT2 antagonist PD123319 (AT2-ant, 20 mg/kg/day, i.p. via osmotic minipump). Treatments started on the day of MI and continued for 7 days. LV ejection fraction (EF) evaluated by echocardiography. Cardiac macrophage infiltration, myocyte cross-sectional area (MCSA) and interstitial collagen fraction (ICF) were studied histopathologically. Spleen CD4 and CD8 T cells as well as circulating interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1) were studied by flow cytometry. MI decreased EF and increased MCSA and ICF, and these changes were associated with increased macrophage infiltration of the heart, CD4 and CD8 T cells in the spleen and serum levels of IL-6 and MCP-1. ARB significantly improved cardiac function and remodeling as indicated by increased EF and decreased MCSA and ICF and also suppressed the post-MI inflammatory response as evidenced by decreased macrophages, CD4 and CD8 T cells and serum cytokines. The effects of ARB were significantly diminished by the AT2-ant (Table). Systolic blood pressure and infarct size were similar in all groups. We concluded that ARB protects against ischemia-induced myocardial injury. The anti-inflammatory action of AT2 may contribute to the cardioprotective effects of ARB.
- © 2012 by American Heart Association, Inc.