Level of β-Adrenergic Receptor Kinase 1 Inhibition Determines Degree of Cardiac Dysfunction After Chronic Pressure Overload–Induced Heart Failure

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Abstract
Background— Heart failure is characterized by abnormalities in β-adrenergic receptor (βAR) signaling, including increased level of myocardial βAR kinase 1 (βARK1). Our previous studies have shown that inhibition of βARK1 with the use of the Gβγ sequestering peptide of βARK1 (βARKct) can prevent cardiac dysfunction in models of heart failure. Because inhibition of βARK activity is pivotal for amelioration of cardiac dysfunction, we investigated whether the level of βARK1 inhibition correlates with the degree of heart failure. Methods and Results— Transgenic (TG) mice with varying degrees of cardiac-specific expression of βARKct peptide underwent transverse aortic constriction (TAC) for 12 weeks. Cardiac function was assessed by serial echocardiography in conscious mice, and the level of myocardial βARKct protein was quantified at termination of the study. TG mice showed a positive linear relationship between the level of βARKct protein expression and fractional shortening at 12 weeks after TAC. TG mice with low βARKct expression developed severe heart failure, whereas mice with high βARKct expression showed significantly less cardiac deterioration than wild-type (WT) mice. Importantly, mice with a high level of βARKct expression had preserved isoproterenol-stimulated adenylyl cyclase activity and normal βAR densities in the cardiac membranes. In contrast, mice with low expression of the transgene had marked abnormalities in βAR function, similar to the WT mice. Conclusions— These data show that the level of βARK1 inhibition determines the degree to which cardiac function can be preserved in response to pressure overload and has important therapeutic implications when βARK1 inhibition is considered as a molecular target.