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β1-Adrenergic Receptor and Sphingosine- 1-Phosphate Receptor 1 Reciprocal Down-Regulation Influences Cardiac Hypertrophic Response and Progression Toward Heart Failure: Protective Role of S1PR1 Cardiac Gene Therapy
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.
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.
Publication Date
08/10/2013
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(c) 2013 The Authors. Full-text reproduced in accordance with the publisher's self-archiving policy.
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openAccess
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09/08/2013
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Abstract
The Sphingosine-1-phosphate receptor 1 (S1PR1) and β1-adrenergic receptor
(β1AR) are G protein-coupled receptors (GPCRs) expressed in the heart. These two GPCRs have
opposing actions on adenylyl cyclase due to differential G protein-coupling. Importantly, both of
these receptors can be regulated by the actions of GPCR kinase-2 (GRK2), which triggers
desensitization and down-regulation processes. Although, classical signaling paradigms suggest
that simultaneous activation of β1ARs and S1PR1s in a myocyte would simply be opposing action
on cAMP production, in this report we have uncovered a direct interaction between these two
receptors with a regulatory involvement of GRK2.
In HEK293 cells overexpressing both β1AR and S1PR1, we
demonstrate that β1AR down-regulation can occur after sphingosine 1-phosphate (S1PR1 agonist)
stimulation while S1PR1 down-regulation can be triggered by isoproterenol (βAR agonist)
treatment. This cross-talk between these two distinct GPCRs appears to have physiological
significance since they interact and show reciprocal regulation in mouse hearts undergoing chronic
βAR stimulation and also in a rat model of post-ischemic heart failure (HF).
We demonstrate that restoring cardiac plasma membrane levels of S1PR1
produce beneficial effects counterbalancing deleterious β1AR overstimulation in HF.
Version
Accepted manuscript
Citation
Cannavo A, Rengo G, Liccardo D et al (2013) β1-Adrenergic Receptor and Sphingosine-
1-Phosphate Receptor 1 Reciprocal Down-Regulation Influences Cardiac Hypertrophic Response
and Progression Toward Heart Failure: Protective Role of S1PR1 Cardiac Gene Therapy.
Circulation. 128(15): 1612–1622.
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Article