β ₁ -Adrenergic Receptor and Sphingosine-1-Phosphate Receptor 1 (S1PR1) Reciprocal Downregulation Influences Cardiac Hypertrophic Response and Progression to Heart Failure

Abstract

Background 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. Methods and Results 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). Conclusions We demonstrate that restoring cardiac plasma membrane levels of S1PR1 produce beneficial effects counterbalancing deleterious β1AR overstimulation in HF.

Adrenergic Receptor Kinase C-Terminal Peptide Gene-Therapy Improves 2-Adrenergic Receptor-Dependent Neoangiogenesis after Hindlimb Ischemia

“…We used 6 and 24 hours of fenoterol stimulation to assess the EC function. Before fenoterol stimulation, some cells were pretreated for 30 minutes with the highly selective b 2 AR-antagonist ICI 118551 [(2R,3S)-1-[(7-methyl-2,3-dihydro-1H-inden-4-yl)oxy]-3-(propan-2-ylamino)butan-2-ol] (IC 50 value: 1.2 nM (K i ); 10 mM), as previously reported elsewhere (Cannavo et al, 2013c).…”

“…Confocal microscopy studies were performed as previously described elsewhere (Cannavo et al, 2013c). After fixation with 3% paraformaldehyde, cells were incubated with an anti-b 2 AR antibody (1:200 anti-rabbit IgG; Santa Cruz Biotechnology) in 1% bovine serum albumin.…”

Sphingosine-1-Phosphate as a Potential Target for the Treatment of Myocardial Infarction

“…Patients with acute MI have lower plasma S1P levels than healthy subjects, 35-37 an observation recently confirmed in a mouse model. 38 This decrease contrasts with the increased plasma S1P levels seen within 1 min of transient ischemia mediated by short periods of coronary vessel occlusion in humans. 39 In addition, a significant correlation is observed between angiographically determined coronary artery disease and S1P levels, which rise with the degree of stenosis.…”

“…SPK and S1P1 receptor mRNAs are decreased in the non-infarcted tissue after MI; this decrease is associated with a gradual loss of S1P1 receptor protein 38 and a decline of SPK activity in chronic post-MI remodeling. 45 These observations led to the hypothesis that S1P1 signaling is impaired during remodeling of the non-infarcted ventricle and that enhancing S1P signaling would ameliorate ventricular dysfunction.…”

“…The authors of the study hypothesized that the favorable action of S1P1 overexpression were caused by either a direct cardioprotective effect or an increased angiogenic response that promoted an adaptive, angiogenesis-dependent LV hypertrophy instead of a transition to a maladaptive state. 38 Among other potentially deleterious effects of S1P, it is worth mentioning that this lipid induces contraction of valvular interstitial cells from porcine aortic valves and leads to the formation of nodules via S1P2 receptors, effects that might eventually be associated with valve dysfunction. 65 S1P is also known to constrict coronary arteries, 66,67 although this constriction is weaker than that of other vessels, and vasorelaxing responses have also been reported.…”