Protective role of AT₂ and B₁ receptors in kinin B₂-receptor-knockout mice with myocardial infarction

AT₂Rs [AngII (angiotensin II) type 2 receptors] contribute to the cardioprotective effects of angiotensin II receptor blockers, possibly via kinins acting on the B₁R (B₁ receptor) and B₂R (B₂ receptor). Recent studies have shown that a lack of B₂R up-regulates B₁R and AT₂R; however, the pathophysiological relevance of such an event remains unclear. We hypothesized that up-regulation of AT₂R and B₁R compensates for the loss of B₂R. Blockade of AT₂R and/or B₁R worsens cardiac remodelling and dysfunction following MI (myocardial infarction) in B₂R^−/− (B₂-receptor-knockout mice). B₂R^−/− mice and WT (wild-type) controls were subjected to sham MI or MI and treated for 4 weeks with (i) vehicle, (ii) a B₁R-ant (B₁R antagonist; 300 μg/kg of body weight per day), (iii) an AT₂R-ant [AT₂ receptor antagonist (PD123319); 20 mg/kg of body weight per day], or (iv) B₁R-ant+AT₂R-ant. B₂R^−/− mice had a greater MCSA (myocyte cross-sectional area) and ICF (interstitial collagen fraction) at baseline and after MI compared with WT controls. Cardiac function and increase in macrophage infiltration, TGFβ₁ (transforming growth factor β₁) expression and ERK1/2 (extracellular-signal-regulated kinase 1/2) phosphorylation post-MI were similar in both strains. Blockade of AT₂R or B₁R worsened cardiac remodelling, hypertrophy and dysfunction associated with increased inflammation and ERK1/2 phosphorylation and decreased NO excretion in B₂R^−/−mice, which were exacerbated by dual blockade of B₁R and AT₂R. No such effects were seen in WT mice. Our results suggest that, in the absence of B₂R, both B₁R and AT₂R play important compensatory roles in preventing deterioration of cardiac function and remodelling post-MI possibly via suppression of inflammation, TGFβ₁ and ERK1/2 signalling.