Fractalkine depresses cardiomyocyte contractility.
BACKGROUND
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.


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 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.


RESULTS
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.


CONCLUSIONS
Fractalkine depresses myocyte contractility by mechanisms downstream of intracellular calcium.
Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan, USA.
David
D
Taube
Jiang
J
Xu
Xiao-Ping
XP
Yang
Albertas
A
Undrovinas
Edward
E
Peterson
Pamela
P
Harding
D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D054428:Chemokine CX3CL1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology; D015870:Gene Expression; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects* / Q000235:genetics; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics; D019210:Troponin I / Q000378:metabolism
D000073883:CX3C Chemokine Receptor 1; D002316:Cardiotonic Agents; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine; D058309:Receptors, Prostaglandin E, EP4 Subtype; D019210:Troponin I; D015232:Dinoprostone; D007545:Isoproterenol; D002118:Calcium