β2-Adrenergic Receptor Signaling in the Cardiac Myocyte is Modulated by Interactions With CXCR4

Abstract

Chemokines are small secreted proteins with chemoattractant properties that play a key role in inflammation, metastasis, and embryonic development. We previously demonstrated a non-chemotactic role for one such chemokine pair, stromal cell-derived factor-1α (SDF-1α) and its G-protein coupled receptor (GPCR), CXCR4. SDF-1/CXCR4 are expressed on cardiac myocytes and have direct consequences on cardiac myocyte physiology by inhibiting contractility in response to the non-selective β-adrenergic receptor (βAR) agonist, isoproterenol. Due to the importance of β-adrenergic signaling in heart failure pathophysiology, we investigated the underlying mechanism involved in CXCR4 modulation of βAR signaling. Our studies demonstrate activation of CXCR4 by SDF-1 leads to a decrease in βAR-induced PKA activity as assessed by cAMP accumulation and PKA-dependent phosphorylation of phospholamban (PLB), an inhibitor of SERCA2a. We determined CXCR4 regulation of βAR downstream targets is β2AR dependent. We demonstrated a physical interaction between CXCR4 and β2AR as determined by co-immunoprecipitation, confocal microscopy and BRET techniques. The CXCR4-β2AR interaction leads to G-protein signal modulation and suggests the interaction is a novel mechanism for regulating cardiac myocyte contractility. Chemokines are physiologically and developmentally relevant to myocardial biology and represent a novel receptor class of cardiac modulators. The CXCR4-β2AR complex could represent a hitherto unknown target for therapeutic intervention.

Potential of gene therapy as a treatment for heart failure

“…SDF1 was shown to decrease myocardial contractility ex vivo and on cardiomyocytes (82). One recent report has shown increased ischemia-reperfusion injury in rat hearts overexpressing CXCR4 (83), while another report investigated the modulation of β-AR signaling by SDF1 and CXCR4 (84), raising interrogations over the potential complex interaction between these chemokines and the cardiovascular system.…”

Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function

“…ARs are also known to be able to form heteromeric receptor complexes (29)(30)(31)(32)(33)(34)(35), and recent evidence suggests that AR may also be able to form heteromeric complexes with chemokine receptors (36)(37)(38). Thus, we studied whether α 1 -AR and CXCR4 may interact on the cell surface of vascular smooth muscle cells through the formation of heteromeric receptor complexes.…”

Autologous Concentrate Bone Marrow Cell Therapy for Ischemic Cardiomyopathy Unsuitable for Revascularization: Feasibility Study

“…Platelets produce several factors as VEGF, SDF-1, that are important for homing, differentiation of endothelial progenitor cell toward endothelial cell and mobilization of cardiac stem cells for myocardial repair [24,25]. Platelets promote angiogenesis and differentiation of CD34+ in endothelial cells [23,26]. Bone marrow stem cells have an important role in the process to repair and protect the ischemic myocardium [27].…”

“…Cytokines (e.g., VEGF, SDF-1α, PDGF) are triggered by the ischemic events and play a major role in the interactions between cells, during the process to restore the damaged myocardium and in the evolution of hibernation toward apoptosis [19]. VEGF promote angiogenesis, improves cardiac function and is involved in the repair of the ischemic myocardium [20][21][22][23]. SDF-1α has inotropic action [25].…”