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ß1-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.

Authors: Cannavo, Alessandro  Rengo, Giuseppe  Liccardo, Daniela  Pagano, Gennaro  Zincarelli, Carmela  De Angelis, Maria Carmen  Puglia, Roberto  Di Pietro, Elisa  Rabinowitz, Joseph E  Barone, Maria Vittoria  Cirillo, Plinio  Trimarco, Bruno  Palmer, Timothy M  Ferrara, Nicola  Koch, Walter J  Leosco, Dario  Rapacciuolo, Antonio 
Citation: Cannavo A, etal., Circulation. 2013 Oct 8;128(15):1612-22. doi: 10.1161/CIRCULATIONAHA.113.002659. Epub 2013 Aug 22.
Pubmed: (View Article at PubMed) PMID:23969695
DOI: Full-text: DOI:10.1161/CIRCULATIONAHA.113.002659


BACKGROUND: The sphingosine-1-phosphate receptor 1 (S1PR1) and ß1-adrenergic receptor (ß1AR) 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 ß1ARs 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.
METHODS AND RESULTS: In HEK (human embryonic kidney) 293 cells overexpressing both ß1AR and S1PR1, we demonstrated that ß1AR downregulation can occur after stimulation with sphingosine-1-phosphate (an S1PR1 agonist), whereas S1PR1 downregulation can be triggered by isoproterenol (a ß-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 ß-adrenergic receptor stimulation and in a rat model of postischemic heart failure.
CONCLUSIONS: We demonstrate that restoration of cardiac plasma membrane levels of S1PR1 produces beneficial effects that counterbalance the deleterious ß1AR overstimulation in heart failure.

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CRRD Object Information
CRRD ID: 13792712
Created: 2018-09-21
Species: All species
Last Modified: 2018-09-21
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.