Deletion of the β2-adrenergic receptor prevents the development of cardiomyopathy in mice.
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.
Department of Pediatrics, Stanford University, Stanford, CA, USA.
Giovanni
G
Fajardo
Mingming
M
Zhao
Takashi
T
Urashima
Sara
S
Farahani
Dong-Qing
DQ
Hu
Sushma
S
Reddy
Daniel
D
Bernstein
D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D056966:Excitation Contraction Coupling / Q000187:drug effects / Q000235:genetics; D017353:Gene Deletion; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism
D058672:Adrenergic beta-2 Receptor Antagonists; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D018343:Receptors, Adrenergic, beta-2; C090114:cysteine and glycine-rich protein 3; D002118:Calcium
Adrenergic receptors; Cardiomyopathy; Excitation–contraction coupling; Signal transduction