Abstract 343: Upregulated S1P Lyase Exerts Cardioprotective Effects through Inhibiting S1P/HIF-1a-Mediated Oxidative/Nitrative Stress during Myocardial Ischemia/Reperfusion
Sphingosine-1-phosphate (S1P) signaling directs a diverse array of biological processes, such as anti-apoptosis, promoting in[[Unable to Display Character: ﬂ]]ammatory, and inducing fibrosis. Therefore, S1P levels need to be tightly controlled through the delicate interplay of its generating enzymes and its degrading enzymes. S1P lyase (SPL1) is a stress-activated enzyme responsible for irreversible S1P catabolism. This study was designed to determine the role of SPL1 in ischemia/reperfusion (I/R) induced cardiac dysfunction and the underlying mechanisms. Mice were subjected to 40 minutes left coronary artery occlusion followed by reperfusion for 24 hours, 1 week, or 4 weeks. First, we observed that SPL1 expression in cardiac tissue was upregulated by about 4-fold in response to I/R (n=6, P<0.01 versus sham). Further, oral administration of THI (an SPL1 inhibitor, 25 mg/L, daily) increased plasma S1P level and deteriorated I/R-induced apoptosis and fibrosis determined 1 week after I/R (all P<0.05 versus I/R + saline group), and cardiac dysfunction (ejection fraction: 39.1 ± 3.1% in I/R + THI group versus 50.7 ± 2.8% in I/R + saline group determined 4 weeks after I/R, P<0.05). After 1 week of I/R, hearts from THI-fed mice exhibited increased hypoxia-inducible factor-1α (HIF-1α) expression, along with significant oxidative/nitrative damage as evidenced by gp91phox, inducible nitric oxide synthase (iNOS), and 3-nitrotyrosine abundance (all P<0.05 versus vehicle). To define the underlying mechanisms of SPL1 in I/R-induced heart injury, neonatal rat ventricular myocytes were cultured and submitted to hypoxia/reoxygenation (H/R, 9 hours/3 hours) with or without THI treatment. Importantly, THI significantly increased gp91phox, iNOS, and 3-nitrotyrosine level, as well as apoptosis (n=8, all P<0.05 versus H/R), all of which were inhibited by pretreatment with HIF-1α siRNA (all P<0.05 versus scramble RNA). The present study demonstrated for the first time that SPL1 is remarkably upregulated during I/R and protects heart from I/R-induced S1P/HIF-1α-mediated oxidative/nitrative stress, suggesting SPL1 as a potential targets of therapy for ischemic heart disease.
- © 2013 by American Heart Association, Inc.