Deletion of the β2-adrenergic receptor prevents the development of cardiomyopathy in mice.

Abstract

Beta adrenergic receptor (β-AR) subtypes act through diverse signaling cascades to modulate cardiac function and remodeling. Previous in vitro studies suggest that β1-AR signaling is cardiotoxic whereas β2-AR signaling is cardioprotective, and may be the case during ischemia/reperfusion in vivo. The objective of this study was to assess whether β2-ARs also play a cardioprotective role in the pathogenesis of non-ischemic forms of cardiomyopathy. To dissect the role of β1 vs β2-ARs in modulating MLP (Muscle LIM Protein) cardiomyopathy, we crossbred MLP-/- with β1-/- or β2-/- mice. Deletion of the β2-AR improved survival, cardiac function, exercise capacity and myocyte shortening; by contrast haploinsufficency of the β1-AR reduced survival. Pathologic changes in Ca(2+) handling were reversed in the absence of β2-ARs: peak Ca(2+) and SR Ca(2+) were decreased in MLP-/- and β1+/-/MLP-/- but restored in β2-/-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 β2-/-/MLP-/-. The L-type Ca(2+) blocker verapamil significantly decreased cardiac function in β2-/-MLP-/- vs WT. We next tested if the protective effects of β2-AR ablation were unique to the MLP model using TAC-induced heart failure. Similar to MLP, β2-/- mice demonstrated delayed progression of heart failure with restoration of myocyte shortening and peak Ca(2+) and Ca(2+) release. Deletion of β2-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 β2-ARs were found to be cardioprotective, in these two models, β2-AR signaling appears to be deleterious, potentially through negative regulation of Ca(2+) dynamics.

• Authors: Giovanni Fajardo, Mingming Zhao, Takashi Urashima, Sara Farahani, Dong-Qing Hu, Sushma Reddy, Daniel Bernstein
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 63 Pg. 155-64 (Oct 2013) ISSN: 1095-8584 [Electronic] England
• PMID: 23920331 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2013.

Chemical References

• Adrenergic beta-2 Receptor Antagonists
• LIM Domain Proteins
• Muscle Proteins
• Receptors, Adrenergic, beta-2
• cysteine and glycine-rich protein 3
• Calcium

Topics

• Adrenergic beta-2 Receptor Antagonists (pharmacology)
• Animals
• Calcium (metabolism)
• Cardiomyopathies (genetics, metabolism, mortality, pathology)
• Disease Models, Animal
• Disease Progression
• Excitation Contraction Coupling (drug effects, genetics)
• Gene Deletion
• Heart Failure (genetics, metabolism, mortality, pathology)
• LIM Domain Proteins (genetics, metabolism)
• Mice
• Mice, Knockout
• Muscle Proteins (genetics, metabolism)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Receptors, Adrenergic, beta-2 (genetics, metabolism)