Fractalkine Depresses Cardiomyocyte Contractility

Background: Our laboratory reported that male mice with cardiomyocyte-selective knockout of the prostaglandin E-2 EP4 receptor sub-type (EP4 KO) exhibit reduced cardiac function. Gene array on left ventricles (LV) showed increased fractalkine, a chemokine implicated in heart failure. We therefore hypothesized that fractalkine is regulated by PGE(2) and contributes to depressed contractility via alterations in intracellular calcium.Methods: Fractalkine was measured in LV of 28-32 week old male EP4 KO and wild type controls (WT) by ELISA and the effect of PGE(2) on fractalkine secretion was measured in cultured neonatal cardiomyocytes and fibroblasts. The effect of fractalkine on contractility and intracellular calcium was determined in Fura-2 AM-loaded, electrical field-paced cardiomyocytes. Cardiomyocytes (AVM) from male C57Bl/6 mice were treated with fractalkine and responses measured under basal conditions and after isoproterenol (Iso) stimulation.Results: LV fractalkine was increased in EP4 KO mice but surprisingly, PGE(2) regulated fractalkine secretion only in fibroblasts. Fractalkine treatment of AVM decreased both the speed of contraction and relaxation under basal conditions and after Iso stimulation. Despite reducing contractility after Iso stimulation, fractalkine increased the Ca2+ transient amplitude but decreased phosphorylation of cardiac troponin I, suggesting direct effects on the contractile machinery.Conclusions: Fractalkine depresses myocyte contractility by mechanisms downstream of intracellular calcium.