A sphingosine kinase 1 mutation sensitizes the myocardium to ischemia/reperfusion injury

Department of Medicine, University of California, San Francisco, San Francisco, California, United States
Cardiovascular Research (Impact Factor: 5.94). 10/2007; 76(1):41-50. DOI: 10.1016/j.cardiores.2007.05.029
Source: PubMed


Sphingosine kinase (SphK) is a key enzyme in the synthesis of sphingosine 1-phosphate (S1P), a bioactive sphingolipid. SphK is involved in ischemic preconditioning (IPC). To date no studies in genetically altered animals have examined the role of SphK1 in myocardial ischemia/reperfusion (IR) injury and IPC.
Wild-type and SphK1 null mouse hearts were subjected to IR (50 min global ischemia and 40 min reperfusion) in a Langendorff apparatus. IPC consisted of 2 min of global ischemia and 2 min of reperfusion for two cycles. At baseline, there were no differences in left ventricular developed pressure (LVDP), +/-dP/dtmax, and LV end-diastolic pressure (EDP) between SphK1 mutant and wild-type (WT) mouse hearts. In the mutants, total SphK enzyme activity was reduced by 44% and S1P levels were decreased by 41%. SphK1 null hearts subjected to IR exhibited more cardiac damage compared with WT: LVDP and +/-dP/dtmax decreased, LVEDP increased, and infarct size increased (n=6, P<0.05). Apoptosis was markedly enhanced in SphK1 mutant IR mouse hearts. IPC was cardioprotective in WT hearts, but this protection appeared to be ineffective in SphK1 null hearts. There was no change in infarct size in the IPC+IR group compared to the IR group in the null hearts (50.1+/-5.0% vs 45.0+/-3.8%, n=6, P=NS). IPC remained ineffective in the null hearts even when the index ischemia time was shortened by 10 min.
Deletion of the SphK1 gene sensitizes the myocardium to IR injury and appears to impair the protective effect of IPC. These data provide the first genetic evidence that the SphK1-S1P pathway is a critical mediator of IPC and cell survival.

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Available from: Holly Hoover, May 01, 2014
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    • "S1P – sphingosine-1-phosphate, SA1P – sphinganine-1-phosphate. to a large extent prevents decrease in the enzyme activity and myocardial S1P level upon ischemia/reperfusion [17]. Consistently, pharmacological or genetic inhibition of SPHK1 abolished IPCinduced cardioprotection in the murine heart [13] [16]. Vessey et al. [18] suggested that the mechanism of IPC involves export of produced S1P from cardiomyocytes to the extracellular space and stimulation of S1PRs. "
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    ABSTRACT: Sphingosine-1-phosphate (S1P) is a cardioprotective sphingolipid present at high concentration in plasma and blood cells. However, effect of the myocardial infarction on S1P metabolism in blood is poorly recognized. Therefore, we aimed to examine the dynamics of changes in concentration of sphingolipids in blood of patients with acute ST-segment elevation myocardial infarction (STEMI). The study was performed on two groups of subjects: healthy controls (n=32) and patients with STEMI (n=32). In the latter group blood was taken upon admission to intensive heart care unit, and then on the second, fifth and thirtieth day, and approximately two years after admission. STEMI patients showed decreased plasma S1P concentration and accumulation of free sphingoid bases and their 1-phosphates in erythrocytes. This effect was already present upon admission, and was maintained for at least thirty days after the infarction. Interestingly, two years post-infarction plasma S1P level recovered only partially, whereas the content of erythrocyte sphingolipids decreased to the values observed in the control subjects. The most likely reason for the observed reduction in plasma S1P level was its decreased release or increased degradation by vascular endothelial cells, as we did not find any evidence for downregulation of S1P synthesis or release by blood cells. We conclude that patients with STEMI are characterized by marked alterations in sphingolipid metabolism in blood which could be a consequence of the infarction itself, the antiplatelet treatment given or both. Our data suggest that cardioprotective action of S1P may be diminished in patients with acute myocardial infarction.
    Prostaglandins & other lipid mediators 10/2013; 106. DOI:10.1016/j.prostaglandins.2013.10.001 · 2.38 Impact Factor
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    • "SphK1 appears to be a protective kinase, as over expression of SphK1 increases intracellular S1P content and promotes cell growth and survival [21–23]. Indeed, study of SphK1 null (KO) mice demonstrated that the absence of SphK1 sensitizes the myocardium to I/R injury and results in the loss of both IPC and IPOST [24,25]. In a study of hearts from SphK2 KO mice it was shown that they are also more sensitive to I/R injury in an isolated perfused heart model, and have a diminished response to IPC [26]. "
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    ABSTRACT: Background We investigated the hypothesis that postconditioning by FTY720 (FTY) in isolated perfused mouse hearts is independent of the sphingosine 1-phosphate (S1P) pathway. Material/Methods Ex vivo hearts were exposed to postconditioning (POST) by either ischemia or FTY720. Protection against ischemia/reperfusion (IR) injury was measured by recovery of left ventricular developed pressure (LVDP) and infarct size. Results FTY effectively postconditioned (POST) ex vivo hearts against ischemia/reperfusion (IR) injury as measured by recovery of LVDP and a low infarct size. FTY protection, unlike S1P but like sphingosine (Sph), was insensitive to inhibition of S1P G-Protein Coupled Receptors (GPCRs) or inhibition of PI3 kinase. Protection by FTY and Sph was however blocked by inhibitors of PKA and PKG. Thus, FTY follows the same cardioprotective pathway as Sph. This was further supported by studies of FTY POST in knockout (KO) mice lacking the SphK2 form of Sph kinase that is needed for phosphorylation of FTY to an S1P analog. In the absence of SphK2, FTY (and Sph) POST was still cardioprotective. This differed from the effect of SphK2 KO on protection by ischemic POST (IPOST). IPOST was not effective in KO hearts. To see if the GPCR signaling pathway to protection is normal in KO hearts, we looked at POST by GPCR agonists S1P and adenosine. Both provided effective protection even in KO hearts suggesting that the problem with IPOST in KO hearts is a low level of S1P available for release during IPOST. Thus, pharmacologic POST with FTY or Sph, like adenosine and S1P, is unaffected in the KO. Conclusions FTY720 administered in vivo might behave in a dual manner showing both S1P-like effects and sphingosine-like effects. It appears that the latter may have been overlooked and may be the more important in aging hearts.
    04/2013; 19:126-32. DOI:10.12659/MSMBR.883877
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    • "The cardioprotective action of S1P 3 seems to involve S1P 3 -mediated activation of endothelial NO synthase (eNOS) [14]. Studies using mice with genetic deletion of SphK1 [24] and SphK2 [25] demonstrated that endogenous S1P, either in perfusates or in cardiac tissues, is cardioprotective ex vivo. S1P generation in the heart is upregulated in response to a transient ischemia, suggesting the contribution of the SphK-S1P axis to ischemic preconditioning and ischemic post-conditioning [26]. "
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    ABSTRACT: Fibrosis is a pathological process characterized by massive deposition of extracellular matrix (ECM) such as type I/III collagens and fibronectin that are secreted by an expanded pool of myofibroblasts, which are phenotypically altered fibroblasts with more contractile, proliferative, migratory and secretory activities. Fibrosis occurs in various organs including the lung, heart, liver and kidney, resulting in loss of normal tissue architecture and functions. Myofibroblasts could originate from multiple sources including tissue-resident fibroblasts, epithelial and endothelial cells through mechanisms of epithelial/endothelial-mesenchymal transition (EMT/EndMT), and bone marrow-derived circulating progenitors called fibrocytes. Emerging evidence in recent years shows that sphingosine-1-phosphate (S1P) acts on several types of target cells and is engaged in pro-fibrotic inflammatory process and fibrogenic process through multiple mechanisms, which include vascular permeability change, leukocyte infiltration, and migration, proliferation and myofibroblast differentiation of fibroblasts. Many of these S1P actions are receptor subtype-specific. In these actions, S1P has multiple cross-talks with other cytokines, particularly transforming growth factor-β (TGFβ), which plays a major role in fibrosis. The cross-talks include the regulation of S1P production through altered expression and activity of sphingosine kinases in fibrotic lesions, altered expression of S1P receptors, and S1P receptor-mediated transactivation of TGFβ signaling pathway. These cross-talks may give rise to a feed-forward, amplifying loop between S1P and TGFβ, and possibly with other cytokines in stimulating fibrogenesis. Another lysophospholipid mediator lysophosphatidic acid has also been recently implicated in fibrosis. The lysophospholipid signaling pathways represent novel, promising therapeutic targets for treating refractory fibrotic diseases. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.
    Biochimica et Biophysica Acta 06/2012; 1831(1). DOI:10.1016/j.bbalip.2012.06.008 · 4.66 Impact Factor
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