Deletion of the beta 2-adrenergic receptor prevents the development of cardiomyopathy in mice

作者：Fajardo Giovanni; Zhao Mingming; Urashima Takashi; Farahani Sara; Hu Dong Qing; Reddy Sushma; Bernstein Daniel^*

来源：Journal of Molecular and Cellular Cardiology, 2013, 63: 155-164.

DOI：10.1016/j.yjmcc.2013.07.016

• Adrenergic receptors
• Cardiomyopathy
• Excitation-contraction coupling
• Signal transduction

Beta adrenergic receptor (beta-AR) subtypes act through diverse signaling cascades to modulate cardiac function and remodeling. Previous in vitro studies suggest that beta 1-AR signaling is cardiotoxic whereas beta 2-AR signaling is cardioprotective, and may be the case during ischemia/reperfusion in vivo. The objective of this study was to assess whether beta 2-ARs also play a cardioprotective role in the pathogenesis of non-ischemic forms of cardiomyopathy. To dissect the role of beta 1 vs beta 2-ARs in modulating MLP (Muscle LIM Protein) cardiomyopathy, we crossbred MLP-/- with beta 1-/- or beta 2-/- mice. Deletion of the beta 2-AR improved survival, cardiac function, exercise capacity and myocyte shortening; by contrast haploinsufficency of the beta 1-AR reduced survival. Pathologic changes in Ca2+ handling were reversed in the absence of beta 2-ARs: peak Ca2+ and SR Ca2+ were decreased in MLP-/- and beta 1 +/-/MLP-/- but restored in beta 2-/- MLP-/-. These changes were associated with reversal of alterations in troponin I and phospholamban phosphorylation. Gi inhibition increased peak and baseline Ca2+, re-capitulating changes observed in the beta 2-/-/MLP-/-. The L-type Ca2+ blocker verapamil significantly decreased cardiac function in beta 2-/- MLP-/- vs WT. We next tested if the protective effects of beta 2-AR ablation were unique to the MLP model using TAC-induced heart failure. Similar to MLP, beta 2-/- mice demonstrated delayed progression of heart failure with restoration of myocyte shortening and peak Ca2+ and Ca2+ release. Deletion of beta 2-ARs prevents the development of MLP-/- cardiomyopathy via positive modulation of Ca2+ 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 beta 2-ARs were found to be cardioprotective, in these two models, beta 2-AR signaling appears to be deleterious, potentially through negative regulation of Ca2+ dynamics.

• 出版日期2013-10