β1-adrenergic receptor and sphingosine-1-phosphate receptor 1 (S1PR1) reciprocal downregulation influences cardiac hypertrophic response and progression to heart failure: protective role of S1PR1 cardiac gene therapy

Cannavo, A. et al. (2013) β1-adrenergic receptor and sphingosine-1-phosphate receptor 1 (S1PR1) reciprocal downregulation influences cardiac hypertrophic response and progression to heart failure: protective role of S1PR1 cardiac gene therapy. Circulation, 128(15), pp. 1612-1622. (doi: 10.1161/CIRCULATIONAHA.113.002659)

Abstract

<b>Background—</b>The sphingosine-1-phosphate receptor 1 (S1PR1) and β1-adrenergic receptor (β1AR) are G-protein–coupled receptors expressed in the heart. These 2 receptors have opposing actions on adenylyl cyclase because of differential G-protein coupling. Importantly, both of these receptors can be regulated by the actions of G-protein–coupled receptor kinase-2, which triggers desensitization and downregulation processes. Although classic signaling paradigms suggest that simultaneous activation of β1ARs and S1PR1s in a myocyte would simply result in opposing action on cAMP production, in this report we have uncovered a direct interaction between these 2 receptors, with regulatory involvement of G-protein–coupled receptor kinase-2.<p></p> <b>Methods and Results—</b>In HEK (human embryonic kidney) 293 cells overexpressing both β1AR and S1PR1, we demonstrated that β1AR downregulation can occur after stimulation with sphingosine-1-phosphate (an S1PR1 agonist), whereas S1PR1 downregulation can be triggered by isoproterenol (a β-adrenergic receptor agonist) treatment. This cross talk between these 2 distinct G-protein–coupled receptors appears to have physiological significance, because they interact and show reciprocal regulation in mouse hearts undergoing chronic β-adrenergic receptor stimulation and in a rat model of postischemic heart failure.<p></p> <b>Conclusions—</b>We demonstrate that restoration of cardiac plasma membrane levels of S1PR1 produces beneficial effects that counterbalance the deleterious β1AR overstimulation in heart failure.<p></p>

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Palmer, Dr Timothy
• Authors: Cannavo, A., Rengo, G., Liccardo, D., Pagano, G., Zincarelli, C., De Angelis, M. C., Puglia, R., Di Pietro, E., Rabinowitz, J. E., Barone, M. V., Cirillo, P., Trimarco, B., Palmer, T. M., Ferrara, N., Koch, W. J., Leosco, D., and Rapacciuolo, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Circulation
• Publisher: Lippincott Williams & Wilkins
• ISSN: 0009-7322
• ISSN (Online): 1524-4539

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