| First Author | Fajardo G | Year | 2013 |
| Journal | J Mol Cell Cardiol | Volume | 63 |
| Pages | 155-64 | PubMed ID | 23920331 |
| Mgi Jnum | J:318158 | Mgi Id | MGI:6858501 |
| Doi | 10.1016/j.yjmcc.2013.07.016 | Citation | Fajardo G, et al. (2013) Deletion of the beta2-adrenergic receptor prevents the development of cardiomyopathy in mice. J Mol Cell Cardiol 63:155-64 |
| abstractText | Beta adrenergic receptor (beta-AR) subtypes act through diverse signaling cascades to modulate cardiac function and remodeling. Previous in vitro studies suggest that beta1-AR signaling is cardiotoxic whereas beta2-AR signaling is cardioprotective, and may be the case during ischemia/reperfusion in vivo. The objective of this study was to assess whether beta2-ARs also play a cardioprotective role in the pathogenesis of non-ischemic forms of cardiomyopathy. To dissect the role of beta1 vs beta2-ARs in modulating MLP (Muscle LIM Protein) cardiomyopathy, we crossbred MLP-/- with beta1-/- or beta2-/- mice. Deletion of the beta2-AR improved survival, cardiac function, exercise capacity and myocyte shortening; by contrast haploinsufficency of the beta1-AR reduced survival. Pathologic changes in Ca(2+) handling were reversed in the absence of beta2-ARs: peak Ca(2+) and SR Ca(2+) were decreased in MLP-/- and beta1+/-/MLP-/- but restored in beta2-/-MLP-/-. These changes were associated with reversal of alterations in troponin I and phospholamban phosphorylation. Gi inhibition increased peak and baseline Ca(2+), recapitulating changes observed in the beta2-/-/MLP-/-. The L-type Ca(2+) blocker verapamil significantly decreased cardiac function in beta2-/-MLP-/- vs WT. We next tested if the protective effects of beta2-AR ablation were unique to the MLP model using TAC-induced heart failure. Similar to MLP, beta2-/- mice demonstrated delayed progression of heart failure with restoration of myocyte shortening and peak Ca(2+) and Ca(2+) release. Deletion of beta2-ARs prevents the development of MLP-/- cardiomyopathy via positive modulation of Ca(2+) due to removal of inhibitory Gi signaling and increased phosphorylation of troponin I and phospholamban. Similar effects were seen after TAC. Unlike previous models where beta2-ARs were found to be cardioprotective, in these two models, beta2-AR signaling appears to be deleterious, potentially through negative regulation of Ca(2+) dynamics. |
