This proposal is based on our prior studies documenting the fundamental importance of sphingosine kinase/sphingosine 1-phosphate (S1P) in myocardial resistance to injury. S1P is a lysophospholipid produced by mast cells, erythrocytes, platelets, cardiac myocytes, and other cell types in de novo biosynthetic pathways and by metabolism of the plasma membrane phospholipid sphingomyelin. Secretion of S1P leads to extensive binding by albumin and plasma lipoproteins and circulation at nanomolar to micromolar concentrations. Extracellular S1P activates plasma membrane G protein-coupled receptors designated S1P1, S1P2, S1P3, S1P4, and S1P5. Endogenous and exogenous S1P also attain functionally relevant intracellular concentrations and regulate viability through unclear mechanisms. A previous NIH grant has supported publication of key observations regarding the prosurvival effects of S1P in cardiac tissue. As summarized in the Progress Report, we determined that pharmacological activation of endogenous S1P production or administration of exogenous S1P was sufficient to decrease infarction and enhance contractility in mouse hearts subjected to ischemia-reperfusion. We developed a rapid and accurate radioassay for measurement of sphingosine kinase activity and established an essential role for the enzyme in preconditioning-induced cardioprotection using pharmacological and gene targeting approaches. By adapting an adult mouse ventricular myocyte model for hypoxia-reoxygenation studies, we showed that S1P1 receptor function, Akt activation, and cell substrates interacting with mitochondria contribute to S1P prosurvival effects. Published findings and compelling preliminary results support our central hypothesis that S1P is a potent mediator of cardioprotection that can reduce acute tissue injury, chronic pathological remodeling, and mortality caused by ischemia and reperfusion. The current proposal is designed to explore new functions of S1P receptor agonism and their mechanisms, and to perform translational studies in animal models.
In Specific Aim 1, we will study effects of the selective S1P1 receptor agonist SEW 2871 in two models of myocardial infarction. Model 1 is the Scavenger Receptor Class B Type I-deficient, hypomorphic apolipoprotein ER61 (SR- BI KO/ApoeR61h/h) mouse provided by Dr. Robert Raffao. These mice rapidly develop occlusive coronary atherosclerosis, myocardial infarction, heart failure, and premature death in response to high-fat feeding. In the second model, we will study the efficacy of SEW 2871 on ventricular dysfunction caused by ligation of the left anterior descending coronary artery in mice provided by Dr. Michael Mann. As part of Aim 1, Dr. Julie Saba will collaborate on translational studies to test the hypothesis that inhibition of S1P lyase, the enzyme that catalyzes irreversible S1P breakdown, leads to cardioprotection by raising intracellular S1P content.
In Specific Aim 2, we shall employ the models studied in Specific Aim 1 to focus on the effects of chronic S1P1 receptor agonism. These studies will include use of sphingosine kinase-1 and -2 null mice, measurements of downstream signaling pathways, determination of the S1P receptor subtypes that mediate chronic signals, and assessment of adhesion molecule expression. Dr. Edward Goetzl will collaborate on studies of S1P1 receptor localization and signaling in myocyte nuclear compartments after chronic agonist exposure, and Dr. Robin Shaw will collaborate in studying the regulation of gap junction trafficking and function by S1P in ventricular myocytes under physiological and stress conditions.
Acute heart attacks claim many lives, as does heart failure resulting from a heart attack, either soon after the acute event or many months-years later. This proposal uses a variety of cellular and biochemical techniques, including genetically altered mice, in order to further our understanding of the mechanisms by which acute heart damage occurs and using this information, to test more effective therapy for this disorder.
|Karliner, Joel S (2014) Selected aspects of cellular responses in heart failure. J Cardiovasc Pharmacol 63:83-4|
|Yeghiazarians, Yerem; Honbo, Norman; Imhof, Isabella et al. (2014) IL-15: a novel prosurvival signaling pathway in cardiomyocytes. J Cardiovasc Pharmacol 63:406-11|
|Wang, Guanying; Kim, Roy Y; Imhof, Isabella et al. (2014) The immunosuppressant FTY720 prolongs survival in a mouse model of diet-induced coronary atherosclerosis and myocardial infarction. J Cardiovasc Pharmacol 63:132-43|
|Karliner, Joel S (2014) Arsonists and firefighters: the perpetual inflammatory civil war for survival. Circulation 129:2368-70|
|Vessey, Donald A; Li, Luyi; Imhof, Isabella et al. (2013) FTY720 postconditions isolated perfused heart by a mechanism independent of sphingosine kinase 2 and different from S1P or ischemic postconditioning. Med Sci Monit Basic Res 19:126-32|
|Karliner, Joel S (2013) Sphingosine kinase and sphingosine 1-phosphate in the heart: a decade of progress. Biochim Biophys Acta 1831:203-12|
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|Vessey, Donald A; Li, Luyi; Jin, Zhu-Qiu et al. (2011) A sphingosine kinase form 2 knockout sensitizes mouse myocardium to ischemia/reoxygenation injury and diminishes responsiveness to ischemic preconditioning. Oxid Med Cell Longev 2011:961059|
|Tao, Rong; Hoover, Holly E; Honbo, Norman et al. (2010) High-density lipoprotein determines adult mouse cardiomyocyte fate after hypoxia-reoxygenation through lipoprotein-associated sphingosine 1-phosphate. Am J Physiol Heart Circ Physiol 298:H1022-8|
|Tao, Rong; Kim, Sun Hee; Honbo, Norman et al. (2010) Minocycline protects cardiac myocytes against simulated ischemiaýýýreperfusion injury by inhibiting poly(ADP-ribose) polymerase-1. J Cardiovasc Pharmacol 56:659-68|
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