S1P lyase: a novel therapeutic target for ischemia-reperfusion injury of the heart

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 300; no. 5; pp. H1753 - H1761
• Main Authors: Bandhuvula, Padmavathi, Honbo, Norman, Wang, Guan-Ying, Jin, Zhu-Qiu, Fyrst, Henrik, Zhang, Meng, Borowsky, Alexander D, Dillard, Lisa, Karliner, Joel S, Saba, Julie D
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.05.2011
• Subjects: Aldehyde-Lyases - antagonists & inhibitors; Aldehyde-Lyases - genetics; Aldehyde-Lyases - physiology; Animals; Correlation analysis; Enzyme Inhibitors - therapeutic use; Food additives; Heart; Ischemia; Kinases; Lysophospholipids - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Mutation - genetics; Myocardial Reperfusion Injury - physiopathology; Myocardial Reperfusion Injury - prevention & control; Myocardium - metabolism; Oxidative Stress - physiology; Phosphorylation; Rodents; Signaling and Stress Response; Sphingosine - analogs & derivatives; Sphingosine - metabolism
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00946.2010

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that promotes cardiomyocyte survival and contributes to ischemic preconditioning. S1P lyase (SPL) is a stress-activated enzyme responsible for irreversible S1P catabolism. We hypothesized that SPL contributes to oxidative stress by depleting S1P pools available for cardioprotective signaling. Accordingly, we evaluated SPL inhibition as a strategy for reducing cardiac ischemia-reperfusion (I/R) injury. We measured SPL expression and enzyme activity in murine hearts. Basal SPL activity was low in wild-type cardiac tissue but was activated in response to 50 min of ischemia (n = 5, P < 0.01). Hearts of heterozygous SPL knockout mice exhibited reduced SPL activity, elevated S1P levels, smaller infarct size, and increased functional recovery after I/R compared with littermate controls (n = 5, P < 0.01). The small molecule tetrahydroxybutylimidazole (THI) is a Federal Drug Administration-approved food additive that inhibits SPL. When given overnight at 25 mg/l in drinking water, THI raised S1P levels and reduced SPL activity (n = 5, P < 0.01). THI reduced infarct size and enhanced hemodynamic recovery in response to 50 min of ischemia and to 40 min of reperfusion in ex vivo hearts (n = 7, P < .01). These data correlated with an increase in MAP kinase-interacting serine/threonine kinase 1, eukaryotic translation initiation factor 4E, and ribosomal protein S6 phosphorylation levels after I/R, suggesting that SPL inhibition enhances protein translation. Pretreatment with an S1P₁ and S1P₃ receptor antagonist partially reversed the effects of THI. These results reveal, for the first time, that SPL is an ischemia-induced enzyme that can be targeted as a novel strategy for preventing cardiac I/R injury.