THE ROLE OF β-ADRENERGIC RECEPTORS IN HEART FAILURE: DIFFERENTIAL REGULATION OF CARDIOTOXICITY AND CARDIOPROTECTION

Abstract

β-adrenergic receptor blockers have demonstrated significant survival benefit and have become standard therapy for adults with dilated cardiomyopathy, although their efficacy in pediatric patients is still unproven. Recent data suggests that the two major cardiac β-adrenergic receptor subtypes (β1 and β2) couple differentially to intracellular signaling pathways regulating contractility and remodeling. This has led some to suggest that the β1 receptor is the "cardiotoxic subtype" whereas the β2 receptor is "cardioprotective." Given this paradigm, there could be situations where subtype selective β-blockade or even subtype selective β-stimulation might be beneficial. However, since most of these studies have been performed in isolated cardiomyocytes, their application to clinical practice is unclear. To better understand the roles of β1- vs. β2-receptors in the pathogenesis of clinical cardiomyopathy, we and others have taken advantage of several well-characterized murine models of cardiovascular disease. These studies demonstrate that β-receptor regulation of the balance between cardioprotection and cardiotoxicity is even more complex than previously appreciated: the role of each β-receptor subtype may vary depending on the specific cardiac stressor involved (e.g. ischemia, pressure overload, genetic mutation, cardiotoxin). Furthermore, the remodeling effects of β-receptor signaling have a temporal component, depending on whether a cardiac stress is acute vs. chronic.

Figure 1

β-adrenergic receptor signaling: the classic (linear) model. Abbreviations: Gs=stimulatory guanylyl nucleotide binding protein; cAMP=cyclic adenosine monophosphate; PKA=protein kinase A.

Figure 2

β-adrenergic receptor signaling crosstalk: the model undergoes revision. Abbreviations: Gs=stimulatory guanylyl nucleotide binding protein; Gi=inhibitory guanylyl nucleotide binding protein; Gβγ = a subunit of Gs which is dissociated from the α subunit after Gs is activated by the β-receptor; cAMP=cyclic adenosine monophosphate; PKA=protein kinase A; ASK1=apoptosis signal-regulating kinase 1; MKK4=mitogen activated protein kinase kinase 4; MAPK=mitogen activated protein kinase; JNK3= c-Jun N-terminal kinase.

Figure 3

β-adrenergic receptor signaling: differential regulation of apoptosis. Gs=stimulatory guanylyl nucleotide binding protein; cAMP=cyclic adenosine monophosphate; PKA=protein kinase A; CaMKII=calcium/calmodulin-dependent protein kinase II; PI3K=phosphoinositide 3-kinase; Akt=protein kinase B; GSK3β=glycogen synthase kinase 3β; Bad=Bcl-2-associated death promoter.

Figure 4

Scaffolding proteins mediate β-receptor crosstalk. Abbrevations: Gs=stimulatory guanylyl nucleotide binding protein; Gi=inhibitory guanylyl nucleotide binding protein; PLB=phospholamban; cAMP=cyclic adenosine monophosphate; PKC=protein kinase C; PKA=protein kinase A; AdCyc=adenylyl cyclase; AKAP79=A-kinase anchor protein 79.