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Fractalkine depresses cardiomyocyte contractility
David Taube1, Jiang Xu, Xiao-Ping Yang
1Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan, USA.
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.
Insights
Prostaglandin E2 EP4 receptor knockout in mice increases fractalkine, a chemokine that depresses heart muscle contractility through mechanisms independent of intracellular calcium.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Prostaglandin Signaling
Background:
- Cardiomyocyte-specific knockout of prostaglandin E2 EP4 receptor (EP4 KO) in male mice leads to reduced cardiac function.
- Gene array analysis revealed increased fractalkine, a chemokine linked to heart failure, in the left ventricles (LV) of EP4 KO mice.
- This suggests a potential role for fractalkine, regulated by PGE2, in depressed cardiac contractility.
Purpose of the Study:
- To investigate the regulation of fractalkine by prostaglandin E2 (PGE2).
- To determine the effect of fractalkine on cardiomyocyte contractility and intracellular calcium.
- To elucidate the mechanisms by which fractalkine influences cardiac function.
Main Methods:
- Measurement of fractalkine levels in the LV of EP4 KO and wild-type (WT) mice using ELISA.
- Assessment of PGE2's effect on fractalkine secretion in cultured neonatal cardiomyocytes and fibroblasts.
- Evaluation of fractalkine's impact on cardiomyocyte contractility and intracellular calcium using Fura-2 AM loading and electrical field stimulation.
Main Results:
- Elevated LV fractalkine was observed in EP4 KO mice; however, PGE2 only regulated fractalkine secretion in fibroblasts.
- Fractalkine treatment of cardiomyocytes reduced contraction and relaxation speeds under basal and isoproterenol-stimulated conditions.
- Fractalkine increased Ca(2+) transient amplitude but decreased cardiac troponin I phosphorylation, indicating direct effects on the contractile apparatus.
Conclusions:
- Fractalkine significantly depresses cardiomyocyte contractility.
- These effects occur through mechanisms downstream of intracellular calcium handling.
- The study identifies fractalkine as a key mediator in EP4 receptor-associated cardiac dysfunction.
