Expression of a β-adrenergic receptor kinase inhibitor reverses dysfunction in failing cardiomyocytes

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Abstract

The spontaneously hypertensive heart failure (SHHF) rat shares numerous functional and molecular characteristics of human heart failure (HF), including impairment of β-adrenergic receptor (AR) signaling with decreased βAR density and coupling to adenylyl cyclase as well as increased βAR kinase (βARK1) levels and activity. We examined the effects of βARK1 inhibition on the signaling and contractile function in failing ventricular myocytes isolated from SHHF rat hearts. This was done by adenoviral-mediated gene transfer of the carboxy-terminal 194 amino acids of βARK1 (βARKct), which acts as an in vivo βARK1 inhibitor. Basal cAMP production was reduced in cells from SHHF rat hearts (n = 4) compared with that found in cells isolated from the hearts of age-matched Sprague-Dawley (SD) control rats (n = 8; SHHF, 2.5 ± 0.2% conversion [3H]adenine to cAMP, versus SD, 4.2 ± 0.2%; P < 0.01), as were cAMP responses to the β-agonist isoproterenol (ISO; SHHF, 5.2 ± 0.2%, versus SD, 7.2 ± 0.4%; P < 0.01). Following βARKct expression, SHHF cardiomyocytes displayed a significant increase in basal (6.6 ± 0.6%, P < 0.01) and ISO-stimulated cAMP production (8.8 ± 0.6%, P < 0.01) versus failing myocytes treated with an empty adenovirus. Concerning contractile function of these cells, βARKct expression produced significant improvement in ISO (10-6 M) stimulated (n = 7 hearts) cell shortening, relaxation, and contraction compared with failing cells treated with the control empty virus (βARKct, 39 ± 11%, 70 ± 18%, and 70 ± 20%, versus empty virus, 1 ± 7%, 5 ± 5%, and 0 ± 7%, respectively). Thus, these data indicate that targeted βARK1 inhibition via genetic manipulation is a powerful therapeutic approach for improving the function of failing cardiomyocytes.

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Eckhart, A. D., & Koch, W. J. (2002). Expression of a β-adrenergic receptor kinase inhibitor reverses dysfunction in failing cardiomyocytes. Molecular Therapy, 5(1), 74–79. https://doi.org/10.1006/mthe.2001.0508

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