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

Jin, Zhu; Zhang, Jianqing; Huang, Yong; Hoover, Holly; Vessey, Donald A.; Karliner, Joel S.

doi:10.1016/j.cardiores.2007.05.029

Cited by 78 publications

(73 citation statements)

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“…Thus, the dramatic decrease of reperfusion injury caused by HDL and S1P may be due to both attenuation of endothelial dysfunction and inhibition of leukocyte extravasation through NO generation. In addition, HDL and S1P may have direct beneficial effects on the myocardium itself, on the basis of the following: (1) both agents protected cardiomyocytes against apoptosis in vitro and in vivo in the present study; (2) sphingosine kinase-1, the key enzyme in S1P synthesis, has been shown to mediate ischemic preconditioning in Langendorff hearts and its genetic deficiency sensitized the myocardium to ischemia/ reperfusion injury 31,32 ; and (3) several S1P receptors are present and functional in cardiomyocytes, 33 which suggests the possibility of direct receptor-mediated antiapoptotic effects. Thus, S1P may protect the heart by acting on both the endothelial cells and cardiomyocytes, and S1P 3 may be involved in both processes.…”

Section: Discussionmentioning

confidence: 67%

High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P ₃ Lysophospholipid Receptor

et al. 2006

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Background-All treatments of acute myocardial infarction are aimed at rapid revascularization of the occluded vessel; however, no clinical strategies are currently available to protect the heart from ischemia/reperfusion injury after restitution of blood flow. We hypothesized that some of the cholesterol transport-independent biological properties of high-density lipoprotein (HDL) implied in atheroprotection may also be beneficial in settings of acute myocardial reperfusion injury. Methods and Results-In an in vivo mouse model of myocardial ischemia/reperfusion, we observed that HDL and its sphingolipid component, sphingosine-1-phosphate (S1P), dramatically attenuated infarction size by Ϸ20% and 40%, respectively. The underlying mechanism was an inhibition of inflammatory neutrophil recruitment and cardiomyocyte apoptosis in the infarcted area. In vitro, HDL and S1P potently suppressed leukocyte adhesion to activated endothelium under flow and protected rat neonatal cardiomyocytes against apoptosis. In vivo, HDL-and S1P-mediated cardioprotection was dependent on nitric oxide (NO) and the S1P 3 lysophospholipid receptor, because it was abolished by pharmacological NO synthase inhibition and was completely absent in S1P 3 -deficient mice. Conclusions-Our data demonstrate that HDL and its constituent, S1P, acutely protect the heart against ischemia/ reperfusion injury in vivo via an S1P 3 -mediated and NO-dependent pathway. A rapid therapeutic elevation of S1P-containing HDL plasma levels may be beneficial in patients at high risk of acute myocardial ischemia. Key Words: lipoproteins Ⅲ inflammation Ⅲ apoptosis Ⅲ endothelium Ⅲ sphingolipids Ⅲ microcirculation Ⅲ reperfusion T he main therapeutic goals in patients with acute myocardial infarction are to minimize myocardial damage, improve cardiac repair, and reduce myocardial remodeling. State-of-the-art therapy is rapid reperfusion of the infarcted myocardium through revascularization of the occluded vessel. However, the benefit of reperfusion is compromised by the endothelial injury and inflammation that follow reinstitution of blood flow, leading to additional myocardial damage, a process termed "ischemia/reperfusion injury." Despite all efforts to prevent the sequelae of reperfusion injury in Clinical Perspective p 1409 patients, 1 there are currently no clinical strategies available to effectively protect cardiac tissue from the inflammatory damage inherent to reperfusion. 2 High-density lipoproteins (HDLs) are the most powerful independent negative predictor of cardiovascular events evident in all large prospective epidemiological studies. The constituents of the HDL particle that mediate its diverse biological effects are still under investigation. 8 Recently, we and others have identified several sphingolipids, such as sphingosine-1-phosphate (S1P), as constituents of human HDL and have found them responsible for part of the nitric oxide (NO)-mediated vasodilatory effect of HDL. 9 -11 Acute administration of reconstituted HDL has been shown to normalize the en...

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Section: Discussionmentioning

confidence: 67%

High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P ₃ Lysophospholipid Receptor

et al. 2006

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“…Ϫ/Ϫ mice have defects in endothelial barrier functions and are more sensitive to heart injury (59,60). Furthermore, the SIPR agonist FTY720 blocks lymphocyte trafficking, prevents allograft rejection in renal transplants, and reduces multiple sclerosis burden in patients (46).…”

Section: Discussionmentioning

confidence: 99%

Sphingosine 1-Phosphate (S1P) Receptors 1 and 2 Coordinately Induce Mesenchymal Cell Migration through S1P Activation of Complementary Kinase Pathways*

Quint¹,

Ruan²,

Pederson³

et al. 2013

Journal of Biological Chemistry

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Background: Coupling of bone degradation to subsequent bone formation requires recruitment of osteoblast precursors. Results: Osteoclasts produce sphingosine 1-phosphate (S1P), which stimulates mesenchymal (skeletal) stem cell migration by activating kinase signaling pathways. Conclusion: Coupling of bone resorption to bone formation involves S1P-mediated recruitment of osteoblastic cells. Significance: Enhancing kinase signaling in osteoblastic cells may be a novel approach to enhance bone formation.

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“…Even though S1P 2 regulates endothelial cell inflammatory responses (87), its functional significance in atherosclerosis has not been addressed. S1P is produced in the heart during brief periods of ischemia and protects the myocardium (119,120). It also activates the G protein-coupled inwardly rectifying potassium (GIRK) channels at the sinoatrial node and induces bradycardia (121).…”

Section: S1p In Diseasementioning

confidence: 99%

Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy

Proia¹,

Hla²

2015

J. Clin. Invest.

443

438

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IntroductionBioactive lipids, derived from metabolism of plasma membrane lipids, are important mediators of cellular communication in vertebrates. The appearance of bioactive lipid receptors in the vertebrate genomes (1) was coincident with the increased complexity of circulatory, immune, and nervous systems in evolution, suggesting that vertebrates began to use extracellular signaling of lipid mediators for the regulation of sophisticated organ systems. This Review will focus on the lysosphingolipid sphingosine-1-phosphate (S1P) and how the basic understanding of its metabolism, transport, and signaling functions has revealed its role in the pathogenesis of various diseases and allowed rational therapeutic strategies to advance. S1P metabolismSphingosine, the precursor substrate for the synthesis of S1P, is derived by the hydrolysis of ceramide during the sequential degradation of plasma membrane glycosphingolipids and sphingomyelin (refs. 2, 3, and Figure 1). Even though this occurs in various cell compartments, the bulk of sphingosine is generated by degradation in lysosomes. Indeed, the prominence of this lysosomal catabolism pathway is illustrated by the severity of the sphingolipidoses, a family of genetic disorders in which sphingolipid metabolites accumulate (4). The catabolically generated sphingosine is phosphorylated by either of two sphingosine kinases, SPHK1 and SPHK2, to produce S1P. SPHK1 is largely cytoplasmic and can acutely associate with the plasma membranes (5), phagosomes (6), and endosomal vesicles (7), whereas SPHK2 is present cytoplasmically but is predominately in the nucleus (8).While not strictly required for cellular viability (9), the formation of S1P is essential for organismal development (10). The viability of the single Sphk KO mice (10, 11) indicates that the isozymes can partially compensate for each other during development but have nonoverlapping functions. Once formed intracellularly, S1P takes one of three pathways (Figure 1). In one, the sphingosine moiety of S1P is recycled through ceramide synthesis after dephosphorylation by S1P-specific ER phosphatases, SGPP1 and SGPP2 (12, 13). In some mammalian cells, this pathway can account for greater than half of complex sphingolipid synthesis (14).In a second pathway, S1P is irreversibly degraded by S1P lyase, another ER-resident enzyme, into phosphoethanolamine and hexadecenal (15). This reaction facilitates transfer of substrate from the sphingolipid to the glycerolipid pathway via the conversion of hexadecenal by fatty aldehyde dehydrogenase to hexadecanoate, a precursor of palmitoyl-CoA (16), and by the utilization of phosphoethanolamine for phosphatidylethanolamine synthesis (17, 18).In the third pathway, intracellular S1P is released to the extracellular environment, a process that is highly efficient in rbc (19-21), platelets (22), and endothelial cells (19)(20)(21). A specific S1P transporter, SPNS2, is used in endothelial cells for S1P secretion (23). The precise secretion mechanism in rbc has not been established, but ...

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

Abstract: 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.

Cited by 78 publications

References 37 publications

High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P ₃ Lysophospholipid Receptor

High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P ₃ Lysophospholipid Receptor

Sphingosine 1-Phosphate (S1P) Receptors 1 and 2 Coordinately Induce Mesenchymal Cell Migration through S1P Activation of Complementary Kinase Pathways*

Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy

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

Abstract: 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.

Cited by 78 publications

References 37 publications

High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P 3 Lysophospholipid Receptor

High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P 3 Lysophospholipid Receptor

Sphingosine 1-Phosphate (S1P) Receptors 1 and 2 Coordinately Induce Mesenchymal Cell Migration through S1P Activation of Complementary Kinase Pathways*

Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy

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Resources

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High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P ₃ Lysophospholipid Receptor

High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P ₃ Lysophospholipid Receptor