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.
Protective role of AT2 and B1 receptors in kinin B2-receptor-knockout mice with myocardial infarction
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Jiang Xu, Oscar A. Carretero, Liping Zhu, Edward G. Shesely, Nour-Eddine Rhaleb, Xiangguo Dai, Luchen Wang, James J. Yang, Xiao-Ping Yang; Protective role of AT2 and B1 receptors in kinin B2-receptor-knockout mice with myocardial infarction. Clin Sci (Lond) 1 January 2013; 124 (2): 87–96. doi: https://doi.org/10.1042/CS20120341
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