Inhibition of βARK1 restores impaired biochemical β-adrenergic receptor responsiveness but does not rescue CREBA133 induced cardiomyopathy

Abstract A. D. Eckhart, R. C. Fentzke, J. Lepore, R. Lang, H. Lin, R. J. Lefkowitz, W. J. Koch and J. M. Leiden. Inhibition of βARK1 Restores Impaired Biochemical β-Adrenergic Receptor Responsiveness but does not Rescue CREB A133 Induced Cardiomyopathy. Journal of Molecular and Cellular Cardiology (2002) 34 , 669–677. The myocardial β-adrenergic receptor (βAR) 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 βAR signaling system including loss of inotropic reserve. Rapid desensitization of βARs is mediated by the βAR kinase (βARK1), which is upregulated during heart failure. Inhibition of βARK1 activity in the heart via expression of a peptide inhibitor (βARKct) has been shown to enhance myocardial function and to “rescue” several animal models of heart failure. To determine the role of βAR dysfunction in the progression of DCM in the CREB A133 mice, we interbred them with mice expressing the βARKct. Concurrent expression of the βARKct peptide and CREB A133 in mouse hearts resulted in the normalization of elevated βARK1 levels. This biochemical change resulted in partial restoration of isoproterenol-stimulated adenylate cyclase activity as well as improvement in fractional shortening in response to βAR 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 βAR signaling as a key element in its pathological progression and accordingly, the restoration of βAR signaling is not sufficient to prevent the development and progression of all forms of heart failure.