Abstract: AIM:To investigate the role of sphingosine 1-phosphate (S1P) lyase (SPL) in the progression of ischemic heart failure. METHODS: Sixty adult male C57/BL6J mice (25-30 g) were randomly divided into four groups: sham, sham+THI, myocardial infarction (MI)+vehicle, and MI+THI. SPL inhibitor, THI (25 mg/L) was fed with drinking water 24 h after MI or sham operation for 2 weeks. After 4 weeks of MI, cardiac S1P content was tested by ELISA. Cardiac structure and function were evaluated by small animal echocardiography. Heart weight/body weight ratio and cardiac fibrosis were evaluated by masson-trichrome staining, TGF-β expression was tested by Western blot, and mRNA levels of collagen I, collagen III, ANP, BNP and α-SMA were determined by real-time PCR. RESULTS: Compared with MI mice, MI+THI mice showed increased cardiac S1P content (P<0.01), decreased left ventricular ejection fraction (LVEF) (P<0.01) and increased left ventricular end-systolic diameter (LVESD) and end-diastolic diameter (LVEDD) (P<0.05). The HW/BW and cardiac fibrosis were more severe in MI+THI mice (P<0.05). TGF-β, collagen I, collagen III, ANP, BNP and α-SMA levels were significantly increased in MI+THI mice (P<0.01). However, no significant difference was observed in the above changes between sham mice and sham+THI mice. CONCLUSION: SPL inhibition exacerbates post-MI cardiac remodeling and heart failure, which may be related to the upregulated pathological S1P signaling.