title: 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.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  We demonstrate that restoration of cardiac plasma membrane levels of S1PR1 produces beneficial effects that counterbalance the deleterious β1AR overstimulation in heart failure.
authors: Division of Geriatrics, Department of Translational Medical Sciences (A.C., G.R., D.L., G.P., N.F., D.L.), Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases (M.V.B.), and Division of Cardiology, Department of Advanced Biomedical Sciences (M.C.D.A., R.P., E.D.P., P.C., B.T., A.R.), Federico II University, Naples, Italy; Center of Translational Medicine, Temple University, Philadelphia, PA (A.C., J.E.R., W.J.K.); Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Telese Terme (BN), Italy (G.R., C.Z., N.F.); and the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (T.M.P.).
authors: Alessandro
authors: A
authors: Cannavo
authors: Giuseppe
authors: G
authors: Rengo
authors: Daniela
authors: D
authors: Liccardo
authors: Gennaro
authors: G
authors: Pagano
authors: Carmela
authors: C
authors: Zincarelli
authors: Maria Carmen
authors: MC
authors: De Angelis
authors: Roberto
authors: R
authors: Puglia
authors: Elisa
authors: E
authors: Di Pietro
authors: Joseph E
authors: JE
authors: Rabinowitz
authors: Maria Vittoria
authors: MV
authors: Barone
authors: Plinio
authors: P
authors: Cirillo
authors: Bruno
authors: B
authors: Trimarco
authors: Timothy M
authors: TM
authors: Palmer
authors: Nicola
authors: N
authors: Ferrara
authors: Walter J
authors: WJ
authors: Koch
authors: Dario
authors: D
authors: Leosco
authors: Antonio
authors: A
authors: Rapacciuolo
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology / Q000628:therapy; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics; D057809:HEK293 Cells; D006333:Heart Failure / Q000503:physiopathology* / Q000628:therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032386:Myoblasts, Cardiac / Q000166:cytology; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy; D051381:Rats; D011921:Rats, Inbred WKY; D020239:Receptor Cross-Talk / Q000502:physiology; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics* / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: D018342:Receptors, Adrenergic, beta-1; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; D049452:Green Fluorescent Proteins
keywords: genetic therapy; heart failure; hypertrophy; receptors, adrenergic, beta; signal transduction
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