Sphingosine 1-phosphate (S1P) generated by sphingosine kinases (SphK) regulates multiple pathophysiological processes in cardiovascular system. The study was designed to investigate the role of SphK/S1P axis in myocardial infarction (MI) induced heart failure and the underlying mechanisms. Male C57BL/6J mice were subjected to permanent left coronary artery occlusion for 4 weeks. The infarcted heart showed increased SphK1 expression and increased S1P content. S1PR1, the predominant type of S1P receptors expressed in left ventricle, was upregulated by 3-fold in cardiac tissue following MI (n=6, all P<0.05). Further, we observed that S1P significantly activated NF-κB/STAT3 signaling and upregulated pro-inflammatory cytokines (TNF-α and IL-6) expression in a dose-dependent manner in cultured neonatal rat ventricular cardiomyocytes (n=3, all P<0.01), all of which were almost blocked by pretreatment with S1PR1 siRNA or FTY720, a functional S1PR1 inhibitor (n=3, all P<0.01). In vivo, administration of FTY720 (3mg/kg, i.p. daily for 4 weeks) decreased SphK1/S1P/S1PR1 axis, inhibited persistent NF-κB/STAT3 signaling activation and blocked pro-inflammatory cytokines production in post-MI heart. Accordingly, FTY720 remarkably alleviated cardiac fibrosis and dysfunction (ejection fraction: 35.5±3.0% vs. 29.4±2.7% , P<0.05). Intriguingly, administration of SphK2 inhibitor ABC294640 (5mg/kg, i.p. daily for 4 weeks) amplified cardiac SphK1/S1P/S1PR1 axis, augmented NF-κB/STAT3 signaling activation and increased inflammatory cytokines expression. Consequently, SphK2 inhibition reduced survival rate (68.4% vs. 83.3%, P<0.05) and exacerbated cardiac maladaptive structural changes and ventricular dysfunction induced by MI (ejection fraction: 25.4±2.3% vs. 30.4±3.2%, P<0.05). Our results provide the evidence that upregulated SphK1/S1P/S1PR1 axis links persistent NF-κB/STAT3 activation, chronic cardiac inflammation and heart failure progression following MI, whereas SphK2 serves as an endogenous suppressor of pathological S1P signaling. Targeting SphK1/S1P/S1PR1 axis by FTY720 treatment or enhancing SphK2 activity might be a potential therapeutic strategy for ischemic heart failure.