Preclinical Study
Targeted Inhibition of β-Adrenergic Receptor Kinase-1–Associated Phosphoinositide-3 Kinase Activity Preserves β-Adrenergic Receptor Signaling and Prolongs Survival in Heart Failure Induced by Calsequestrin Overexpression

https://doi.org/10.1016/j.jacc.2005.02.062Get rights and content
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Objectives

Desensitization and down-regulation of β-adrenergic receptors (βARs) are prominent features of heart failure largely mediated by increased levels of βAR kinase-1 (βARK1).

Background

β-adrenergic receptor kinase 1 interacts with phosphoinositide-3 kinase (PI3K), and upon agonist stimulation, the βARK1/PI3K complex is recruited to agonist-stimulated βARs. Here we tested the hypothesis that in vivo selective inhibition of βARK1-associated PI3K activity would preserve βAR signaling and, therefore, improve cardiac function and survival in experimental heart failure.

Methods

We used a murine model of heart failure induced by calsequestrin (CSQ) cardiac-specific overexpression; CSQ mice were crossed with mice overexpressing in the heart a catalytically inactive PI3Kγ (PI3Kγinact) to competitively displace endogenous PI3K from βARK1.

Results

Catalytically inactive PI3KγPI3K overexpression in CSQ mice inhibited βARK1-associated PI3K activity, normalized βAR levels, and preserved βAR responsiveness to isoproterenol (ISO). Restoration of βAR signaling via PI3Kγinactoverexpression resulted in marked improvement of cardiac function and a significant prolongation of survival. Importantly, the effects of PI3Kγinactoverexpression were restricted to βAR signaling, because cellular PI3K signaling was unaltered, as shown by the similar activation of multiple downstream signaling pathways in both CSQ and CSQ/PI3Kγinactmice.

Conclusions

These data in the CSQ model of cardiac dysfunction indicate that membrane-targeted PI3K activity plays a detrimental role in heart failure, and its inhibition represents a novel therapeutic approach to ameliorate cardiac dysfunction and improve survival.

Abbreviations and Acronyms

βAR
β-adrenergic receptor
βARK1
βAR kinase-1
cAMP
cyclic adenosine monophosphate
CSQ
calsequestrin
GSK
glycogen synthase kinase 3β
ISO
isoproterenol
MAPKs
mitogen-activated protein kinases
PKB
protein kinase B
PI3K
phosphoinositide-3 kinase
PI3Kγinact
catalytically inactive PI3Kγ
WT
wild type
%FS
percent fractional shortening

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This work was supported by a National Institutes of Health grant to Dr. Rockman (HL-61558).