Fractalkine depresses cardiomyocyte contractility

Our laboratory reported that male mice with cardiomyocyte-selective knockout of the prostaglandin E2 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 th...

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Bibliographic Details
Published in:PloS one 2013-07, Vol.8 (7), p.e69832-e69832
Main Authors: Taube, David, Xu, Jiang, Yang, Xiao-Ping, Undrovinas, Albertas, Peterson, Edward, Harding, Pamela
Format: Article
Language:English
Subjects:
Animals
Biology
Calcium
Calcium (intracellular)
Calcium - metabolism
Calcium-binding protein
Cardiomyocytes
Cardiomyopathy
Cardiotonic Agents - pharmacology
Chemokine CX3CL1 - genetics
Chemokine CX3CL1 - metabolism
Chemokine CX3CL1 - pharmacology
Chemokines
Contraction
CX3C Chemokine Receptor 1
Cytokines
Dinoprostone - pharmacology
Enzyme-linked immunosorbent assay
Fibroblasts
Fractalkine
Fura-2
Gene Expression
Heart
Heart diseases
Heart failure
Heart Ventricles - drug effects
Heart Ventricles - metabolism
Heart Ventricles - physiopathology
Hypertension
Inflammation
Intracellular
Isoproterenol
Isoproterenol - pharmacology
Kinases
Machinery
Machinery and equipment
Male
Measurement methods
Medicine
Mice
Mice, Knockout
Models, Biological
Muscle contraction
Myocardial Contraction - drug effects
Myocardial Contraction - genetics
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Neonates
Phosphorylation
Phosphorylation - drug effects
Prostaglandin E2
Proteins
Receptors, Chemokine - genetics
Receptors, Chemokine - metabolism
Receptors, Prostaglandin E, EP4 Subtype - genetics
Rodents
Stimulation
Transplants & implants
Troponin
Troponin I
Troponin I - metabolism
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Summary:Our laboratory reported that male mice with cardiomyocyte-selective knockout of the prostaglandin E2 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 PGE2 and contributes to depressed contractility via alterations in intracellular calcium. Fractalkine was measured in LV of 28-32 week old male EP4 KO and wild type controls (WT) by ELISA and the effect of PGE2 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. LV fractalkine was increased in EP4 KO mice but surprisingly, PGE2 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 Ca(2+) transient amplitude but decreased phosphorylation of cardiac troponin I, suggesting direct effects on the contractile machinery. Fractalkine depresses myocyte contractility by mechanisms downstream of intracellular calcium.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0069832