Role of B1 and AT2 Receptors in Cardiac Remodeling and Dysfunction in B2 Receptor Knockout Mice with Myocardial Infarction

Activation of angiotensin II type 2 receptors (AT 2 R) contributes to cardioprotective effects of angiotensin receptor blockers, possibly via kinins acting on B 1 and B 2 receptors (B 1 R and B 2 R). Using B 2 R knockout mice (B 2 R−/− on B6;129SF2/J background, which have increased both B 1 R and AT 2 R expression), we tested the hypothesis that AT 2 R and B 1 R compensate for loss of B 2 R and that blockade of AT 2 R and/or B 1 R deteriorates cardiac remodeling and dysfunction in B 2 R−/− mice post myocardial infarction (MI). B 2 R−/− and wild‐type controls (WT) were subjected to sham MI or MI and treated with either vehicle, B 1 R antagonist (B 1 R‐ant, R892, 300 μg/kg/day), AT 2 R‐ant (PD123319, 20 mg/kg/day) or B 1 R‐ant + AT 2 R‐ant for 4 weeks. We found that 1) B 2 R−/− with sham MI had greater LV mass and myocyte cross‐sectional area (MCSA) than WT ( Figure 2) after MI, the increase in MCSA and interstitial collagen fraction (ICF) was greater in B 2 R−/−, but ejection fraction (EF) did not differ from WT; 3) B 1 R‐ant alone but not AT 2 R‐ant further increased MCSA and ICF and decreased EF in B 2 R−/−; and 4) blockade of both B 1 R and AT 2 R increased LV mass, diastolic dimension, MCSA and ICF and decreased EF further. Our results suggest that B 1 R and AT 2 R may play an important role in preventing deterioration of cardiac function and remodeling post‐ MI when B 2 R are absent. This work was supported by NIH grants HL28982, HL078951.