Protective role of AT(2) and B(1) receptors in kinin B(2)-receptor-knockout mice with myocardial infarction.

Abstract

AT(2)Rs [AngII (angiotensin II) type 2 receptors] contribute to the cardioprotective effects of angiotensin II receptor blockers, possibly via kinins acting on the B(1)R (B(1) receptor) and B(2)R (B(2) receptor). Recent studies have shown that a lack of B(2)R up-regulates B(1)R and AT(2)R; however, the pathophysiological relevance of such an event remains unclear. We hypothesized that up-regulation of AT(2)R and B(1)R compensates for the loss of B(2)R. Blockade of AT(2)R and/or B(1)R worsens cardiac remodelling and dysfunction following MI (myocardial infarction) in B(2)R(-/-) (B(2)-receptor-knockout mice). B(2)R(-/-) mice and WT (wild-type) controls were subjected to sham MI or MI and treated for 4 weeks with (i) vehicle, (ii) a B(1)R-ant (B(1)R antagonist; 300 μg/kg of body weight per day), (iii) an AT(2)R-ant [AT(2) receptor antagonist (PD123319); 20 mg/kg of body weight per day], or (iv) B(1)R-ant+AT(2)R-ant. B(2)R(-/-) 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, TGFβ(1) (transforming growth factor β(1)) expression and ERK1/2 (extracellular-signal-regulated kinase 1/2) phosphorylation post-MI were similar in both strains. Blockade of AT(2)R or B(1)R worsened cardiac remodelling, hypertrophy and dysfunction associated with increased inflammation and ERK1/2 phosphorylation and decreased NO excretion in B(2)R(-/-) mice, which were exacerbated by dual blockade of B(1)R and AT(2)R. No such effects were seen in WT mice. Our results suggest that, in the absence of B(2)R, both B(1)R and AT(2)R play important compensatory roles in preventing deterioration of cardiac function and remodelling post-MI possibly via suppression of inflammation, TGFβ(1) and ERK1/2 signalling.

• Authors: Jiang Xu, Oscar A Carretero, Liping Zhu, Edward G Shesely, Nour-Eddine Rhaleb, Xiangguo Dai, Luchen Wang, James J Yang, Xiao-Ping Yang
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 124 Issue 2 Pg. 87-96 (Jan 2013) ISSN: 1470-8736 [Electronic] England
• PMID: 22849668 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 2 Receptor Blockers
• Bradykinin B1 Receptor Antagonists
• Bradykinin B2 Receptor Antagonists
• Cardiotonic Agents
• Imidazoles
• Pyridines
• Receptor, Angiotensin, Type 2
• Receptor, Bradykinin B1
• Receptor, Bradykinin B2
• Transforming Growth Factor beta1
• PD 123319
• Nitric Oxide
• Creatinine

Topics

• Angiotensin II Type 2 Receptor Blockers (pharmacology)
• Animals
• Blood Pressure
• Bradykinin B1 Receptor Antagonists
• Bradykinin B2 Receptor Antagonists
• Cardiotonic Agents (metabolism)
• Creatinine (urine)
• Echocardiography
• Imidazoles (pharmacology)
• Immunohistochemistry
• Mice
• Mice, Knockout
• Myocardial Infarction (metabolism)
• Myocytes, Cardiac (cytology)
• Nitric Oxide (urine)
• Pyridines (pharmacology)
• Real-Time Polymerase Chain Reaction
• Receptor, Angiotensin, Type 2 (metabolism)
• Receptor, Bradykinin B1 (metabolism)
• Receptor, Bradykinin B2 (genetics)
• Signal Transduction (drug effects, physiology)
• Transforming Growth Factor beta1 (metabolism)