Abstract
Stroma cell-derived factor-1α (SDF-1α) is a cardioprotective chemokine, acting through its G-protein coupled receptor CXCR4. In experimental acute myocardial infarction, administration of SDF-1α induces an early improvement of systolic function which is difficult to explain solely by an anti-apoptotic and angiogenic effect. We wondered whether SDF-1α signaling might have direct effects on calcium transients and beating frequency.Primary rat neonatal cardiomyocytes were culture-expanded and characterized by immunofluorescence staining. Calcium sparks were studied by fluorescence microscopy after calcium loading with the Fluo-4 acetoxymethyl ester sensor. The cardiomyocyte enriched cellular suspension expressed troponin I and CXCR4 but was vimentin negative. Addition of SDF-1α in the medium increased cytoplasmic calcium release. The calcium response was completely abolished by using a neutralizing anti-CXCR4 antibody and partially suppressed and delayed by preincubation with an inositol triphosphate receptor (IP3R) blocker, but not with a ryanodine receptor (RyR) antagonist. Calcium fluxes induced by caffeine, a RyR agonist, were decreased by an IP3R blocker. Treatment with forskolin or SDF-1α increased cardiomyocyte beating frequency and their effects were additive. In vivo, treatment with SDF-1α increased left ventricular dP/dtmax.These results suggest that in rat neonatal cardiomyocytes, the SDF-1α/CXCR4 signaling increases calcium transients in an IP3-gated fashion leading to a positive chronotropic and inotropic effect.
Highlights
The chemokine Stroma cell-derived factor-1a (SDF-1a) (Stroma cell-Derived Factor 1a) regulates a variety of cellular processes including cell homing and differentiation through its receptor CXCR4 [1]
We explored the effects of the interaction of SDF-1a with its receptor CXCR4 on neonatal cardiomyocyte calcium transients, in the presence or not, of either ryanodine receptor (RyR) or IP3R blockers
In vivo variables were tested by a two-factor analysis of variance (ANOVA) for repeated measures followed by Scheffe post-hoc tests when overall significance was detected
Summary
The chemokine SDF-1a (Stroma cell-Derived Factor 1a) regulates a variety of cellular processes including cell homing and differentiation through its receptor CXCR4 [1]. SDF-1a is over-expressed in ischemic myocardial tissue [2,3,4] and its observed cardioprotective effects are reported to be exerted through inhibition of cardiomyocyte apoptosis, stem cell recruitment and promotion of angiogenesis [5]. In rodent models of myocardial ischemia, SDF-1a administration has been shown to be associated with an early improvement in ventricular systolic function, which is difficult to explain solely on the basis of improved microcirculation and tissue preservation [5,6]. The dominant mode of intracellular calcium release is gated by ryanodine receptors (RyRs). This process depends on postnatal t-tubules formation and resultant colocalization of dihydropyridine receptors and RyRs [9]. In human end-stage heart failure, RyRs are downregulated and IP3Rs are upregulated [11]. IP3Rs provide an alternative pathway for mobilizing intracellular calcium [11]
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