Inhibition of betaARK1 restores impaired biochemical beta-adrenergic receptor responsiveness but does not rescue CREB(A133) induced cardiomyopathy.
The myocardial beta-adrenergic receptor (betaAR) system plays a key role in dysfunctional signaling and physiology of the failing heart. Recently we described a murine model of dilated cardiomyopathy (DCM) produced by cardiac-specific expression of a dominant negative form of the CREB transcription factor (CREB(A133) mice). CREB(A133) mice display abnormalities within the betaAR signaling system including loss of inotropic reserve. Rapid desensitization of betaARs is mediated by the betaAR kinase (betaARK1), which is upregulated during heart failure. Inhibition of betaARK1 activity in the heart via expression of a peptide inhibitor (betaARKct) has been shown to enhance myocardial function and to "rescue" several animal models of heart failure. To determine the role of betaAR dysfunction in the progression of DCM in the CREB(A133) mice, we interbred them with mice expressing the betaARKct. Concurrent expression of the betaARKct peptide and CREB(A133) in mouse hearts resulted in the normalization of elevated betaARK1 levels. This biochemical change resulted in partial restoration of isoproterenol-stimulated adenylate cyclase activity as well as improvement in fractional shortening in response to betaAR stimulation. Interestingly, the progression of DCM and premature mortality was not altered. Therefore, the pathogenesis of DCM in CREB(A133) mice does not appear to involve abnormal betaAR signaling as a key element in its pathological progression and accordingly, the restoration of betaAR signaling is not sufficient to prevent the development and progression of all forms of heart failure.
Eckhart
Andrea D
AD
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Fentzke
Richard C
RC
Lepore
John
J
Lang
Roberto
R
Lin
Hua
H
Lefkowitz
Robert J
RJ
Koch
Walter J
WJ
Leiden
Jeffrey M
JM
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D004452:Echocardiography; D006439:Hemodynamics; D051379:Mice; D008822:Mice, Transgenic; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D016277:Ventricular Function, Left; D051552:beta-Adrenergic Receptor Kinases
D017362:Cyclic AMP Response Element-Binding Protein; D011943:Receptors, Adrenergic, beta; D009320:Atrial Natriuretic Factor; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases