Abstract 2963: The Absence of the Physiological Antagonist of Transforming Growth Factor-Beta, BAMBI, Promotes Alterations in Myocardial Beta-1 Adrenergic Signaling
Transforming growth factor-beta (TGF-β) overexpression promotes alterations in β-adrenergic receptor signaling and, as a result, the isoprenaline induced contractile response is affected. The TGF-β antagonist BAMBI (BMP and Activin Membrane Bound Inhibitor) regulates negatively the cardiomyocyte response to this cytokine. The lack of BAMBI in mutant mice results in increased levels of TGF-β signalling activity.
Hypothesis: In the absence of BAMBI the expression and function of myocardial β1-adrenergic receptors are altered.
Methods: In BAMBI KO (KO) and wild type (WT) mice, the gene (q-PCR) and protein (Western Blot) expressions of β1-adrenergic receptor, GRK2, and β-arrestin were analyzed. β1 receptor coupling with proteins Gαs (GTPγS) and production of cAMP in response to isoprenaline were assessed.
Results: Gene expressions of β-adrenergic receptor (WT: 0.31±0.08 vs KO: 0.18±0.08, p<0.05), GRK (WT: 2.14±0.55 vs KO: 1.31±0.70; p<0.05) and β-arrestin (WT: 0.43±0.05 vs KO: 0.36±0.11; p<0.05) were lower in KO mice. These differences were confirmed at the protein level. Gene expression of β1-adrenergic receptor correlated directly with BAMBI’s (r=0.8; p<0.05) and inversely with TGF-β’s (r=0.7; p<0.01). In myocardial membrane preparations, fixation of GTPγS to G-proteins induced by isoprenaline was 126.0±5 % in WT and 104.5±3 % in KO animals (p<0.01). Intracellular accumulation of cAMP in response to the agonist was of 145.9±5 % in WT and 118.3±2 % in KO (p<0.01).
Conclusions: The absence of BAMBI in the myocardium promotes a reduction in the expression of β1-adrenergic receptors and a consequent lower cellular response to the activation with agonists.
(Funding: FIS PI 06/0240).