Cardioprotection mediated by sphingosine-1-phosphate and ganglioside GM-1 in wild-type and PKCε knockout mouse hearts

Jin, Zhu; Zhou, Hui; Zhu, Peili; Honbo, Norman; Mochly‐Rosen, Daria; Messing, Robert O.; Goetzl, Edward J.; Karliner, Joel S.; Gray, Mary O.

doi:10.1152/ajpheart.01029.2001

Cited by 147 publications

(141 citation statements)

References 29 publications

(49 reference statements)

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“…Maulik et al [23] initially showed that GM-1 can reduce I/R injury in an isolated rat heart by Langendorff technique and had suggested that the likely mechanisms included inhibition of calcium overloading and scavenging of free radicals generated during the reperfusion of myocardium. Recent studies by Jin et al [24] have confirmed that GM-1, which enhances endogenous sphingosine-1-phosphate production, reduces cardiac injury through PKCε-dependent intracellular pathways in an isolated mouse heart Langendorff model of ischemia-reperfusion injury.…”

Section: Sphingolipids and Myocardial I/r Injurymentioning

confidence: 92%

“…Unlike ceramide and sphingosine, S1P promotes cell growth, viability, mitosis and angiogenesis either through S1P receptors or intracellularly as a secondary messenger [34]. Jin et al [24] have shown that the cardioprotection conferred by the monoganglioside GM-1, which stimulates SK, is cardioprotective in part through increased generation of S1P. They have also shown that the cardioprotection conferred by myocardial ischemic preconditioning may also be mediated through PKCε mediated increase in SK activity [40].…”

Section: Sphingolipids and Myocardial I/r Injurymentioning

confidence: 99%

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Sphingolipid therapy in myocardial ischemia–reperfusion injury

Gundewar

Lefer

2008

Biochimica et Biophysica Acta (BBA) - General Subjects

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Sphingolipids are known to play a significant physiological role in cell growth, cell differentiation, and critical signal transduction pathways. Recent studies have demonstrated a significant role of sphingolipids and their metabolites in the pathogenesis of myocardial ischemia-reperfusion injury. Our laboratory has investigated the cytoprotective effects of N,N,N-Trimethylsphingosine chloride (TMS), a stable N-methylated synthetic sphingolipid analogue on myocardial and hepatic ischemia reperfusion injury in clinically relevant in vivo murine models of ischemia-reperfusion injury. TMS administered intravenously at the onset of ischemia reduced myocardial infarct size in the wild-type and obese (ob/ob) mice. Following myocardial I/R, there was an improvement in cardiac function in the wild-type mice. Additionally, TMS also decreased serum liver enzymes following hepatic I/R in wild-type mice. The cytoprotective effects did not extend to the ob/ob mice following hepatic I/R or to the db/db mice following both myocardial and hepatic I/R. Our data suggests that although TMS is cytoprotective following I/R in normal animals, the cytoprotective actions of TMS are largely attenuated in obese and diabetic animals which may be due to altered signaling mechanisms in these animal models. Here we review the therapeutic role of TMS and other sphingolipids in the pathogenesis of myocardial ischemia reperfusion injury and their possible mechanisms of cardioprotection.

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Section: Sphingolipids and Myocardial I/r Injurymentioning

confidence: 92%

Section: Sphingolipids and Myocardial I/r Injurymentioning

confidence: 99%

Sphingolipid therapy in myocardial ischemia–reperfusion injury

Gundewar

Lefer

2008

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…Creatine kinase (CK) activity in coronary effluent collected during reperfusion was measured using a commercial kit (Sigma) and corrected for flow rate and wet heart weight. After reperfusion, hearts were perfused with 1% triphenyltetrazolium chloride solution, fixed in 10% neutral buffered formalin, and sectioned (20). Planimetry of viable (stained) and necrotic (unstained) tissue was performed using NIH Image software.…”

Section: Methodsmentioning

confidence: 99%

“…1B). Cardioprotection in association with PKC activation has also been observed after stimulation with pharmacological agents such as adenosine A 1 receptor agonists (15), ␦ 1 -opioid receptor agonists (12,26), ethanol (19,27), sphingosine-1-phosphate (20), and ␣ 1 -adrenergic receptor agonists (9,28). Here we pretreated with PHE at concentrations selective for ␣ 1 -adrenergic receptor stimulation and improved LVDP recovery during reperfusion in wild-type but not PKC⑀ KO hearts (Fig.…”

Section: Normal Base-line Morphology and In Vivo Cardiac Function In mentioning

confidence: 99%

Preservation of Base-line Hemodynamic Function and Loss of Inducible Cardioprotection in Adult Mice Lacking Protein Kinase Cϵ

Gray

Zhou

Schafhalter-Zoppoth

et al. 2004

Journal of Biological Chemistry

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104

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Signaling pathways involving protein kinase C isozymes are modulators of cardiovascular development and response to injury. Protein kinase C⑀ activation in cardiac myocytes reduces necrosis caused by coronary artery disease. However, it is unclear whether protein kinase C⑀ function is required for normal cardiac development or inducible protection against oxidative stress. Protein kinase C␦ activation is also observed during cardiac preconditioning. However, its role as a promoter or inhibitor of injury is controversial. We examined hearts from protein kinase C⑀ knock-out mice under physiological conditions and during acute ischemia reperfusion. Null-mutant and wild-type mice displayed equivalent base-line morphology and hemodynamic function. Targeted disruption of the protein kinase C⑀ gene blocked cardioprotection caused by ischemic preconditioning and ␣ 1 -adrenergic receptor stimulation. Protein kinase C␦ activation increased in protein kinase C⑀ knock-out myocytes without altering resistance to injury. These observations support protein kinase C⑀ activation as an essential component of cardioprotective signaling. Our results favor protein kinase C␦ activation as a mediator of normal growth. This study advances the understanding of cellular mechanisms responsible for preservation of myocardial integrity as potential targets for prevention and treatment of ischemic heart disease.Coronary artery disease and chronic heart failure are important causes of death worldwide. Cellular signaling pathways that regulate cardiovascular development and responses to injury, particularly those involving protein kinase C (PKC) 1 isozymes, are under intense investigation. For example, MochlyRosen et al. (1) found that activation of PKC⑀ translocation in transgenic mouse hearts caused physiological hypertrophy and reduced the size of individual myocytes. In contrast, postnatal inhibition of PKC⑀ translocation produced lethal dilated cardiomyopathy and increased cardiac myocyte volumes (1). Wu et al. (2) later observed that activation of PKC⑀ translocation in G␣ q transgenic hearts improved contractile function. Conversely, inhibition of PKC⑀ translocation converted the G␣ q hypertrophic phenotype to a dilated cardiomyopathy (2). However, no previous investigations established whether PKC⑀ activation was an absolute requirement for normal cardiac growth or whether compensatory changes in the expression of other myocardial proteins developed in the absence of PKC⑀-mediated signaling.Two lines of evidence support the hypothesis that PKC⑀ activation promotes myocardial resistance to injury during periods of oxidative stress. First, both ischemic preconditioning and pharmacological approaches that induce cardioprotection increase PKC⑀ immunoreactivity and kinase function in cell particulate fractions (3). Second, transgenic expression of a constitutively active PKC⑀ (4) or a peptide agonist of PKC⑀ translocation (5) reduces cardiac myocyte necrosis during ischemia reperfusion. However, it is unclear whether PKC⑀ activation represe...

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“…S1P has been shown to activate Akt (14,37,39), which has been associated with cell survival in cardiomyocytes (10,31,38). In addition, S1P has been shown to protect neonatal rat cardiomyocytes and perfused rabbit and mouse hearts from ischemic damage (5,18,19,22). However, neither the receptor subtype nor the signal-transduction pathways mediating these effects has been established, nor has an in vivo protective role for endogenously released S1P been demonstrated.…”

Section: ϫ/ϫmentioning

confidence: 99%

Sphingosine 1-phosphate S1P₂ and S1P₃ receptor-mediated Akt activation protects against in vivo myocardial ischemia-reperfusion injury

Means

Xiao

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

204

185

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(S1P) is released at sites of tissue injury and effects cellular responses through activation of G protein-coupled receptors. The role of S1P in regulating cardiomyocyte survival following in vivo myocardial ischemiareperfusion (I/R) injury was examined by using mice in which specific S1P receptor subtypes were deleted. Mice lacking either S1P 2 or S1P3 receptors and subjected to 1-h coronary occlusion followed by 2 h of reperfusion developed infarcts equivalent to those of wild-type (WT) mice. However, in S1P2,3 receptor double-knockout mice, infarct size following I/R was increased by Ͼ50%. I/R leads to activation of ERK, JNK, and p38 MAP kinases; however, these responses were not diminished in S1P2,3 receptor knockout compared with WT mice. In contrast, activation of Akt in response to I/R was markedly attenuated in S1P2,3 receptor knockout mouse hearts. Neither S1P2 nor S1P3 receptor deletion alone impaired I/R-induced Akt activation, which suggests redundant signaling through these receptors and is consistent with the finding that deletion of either receptor alone did not increase I/R injury. The involvement of cardiomyocytes in S1P2 and S1P3 receptor mediated activation of Akt was tested by using cells from WT and S1P receptor knockout hearts. Akt was activated by S1P, and this was modestly diminished in cardiomyocytes from S1P2 or S1P3 receptor knockout mice and completely abolished in the S1P2,3 receptor double-knockout myocytes. Our data demonstrate that activation of S1P2 and S1P3 receptors plays a significant role in protecting cardiomyocytes from I/R damage in vivo and implicate the release of S1P and receptor-mediated Akt activation in this process.cardioprotection; mitogen-activated kinase; G protein-coupled receptors; infarct SPHINGOSINE 1-PHOSPHATE (S1P) is a bioactive lysophospholipid generated through the breakdown of sphingomyelin. A number of regulated enzymes, including sphingomyelinase and sphingosine kinase, control its formation (40). A role for S1P in regulating cellular responses to injury and inflammation has become increasingly well accepted. In the heart, as in other tissues, sphingomyelinase is activated by ischemia-reperfusion (I/R) (anoxia-reoxygenation) and by cytokines such as TNF-␣, suggesting that sphingolipid metabolites (ceramide, sphingosine, and S1P) are generated and may participate in cellular responses to these interventions (5,8,12,23). Sphingosine kinase has also been shown to be activated by I/R in the heart (18). Although intracellular actions of sphingomyelin metabolites had been examined for many years, the cloning of G protein-coupled receptors with specificity for S1P led to recognition that sphingolipid-mediated responses are effected, in large part, through extracellular activation of cell surface receptors (6,16,26).The S1P receptors, originally classified into the edg receptor family, are now referred to as S1P 1 -S1P 5 . The S1P 1 (edg1), S1P 2 (edg5), and S1P 3 (edg3) receptors are ubiquitously expressed, whereas the expression of S1P 4 and S1P 5 receptors...

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Cardioprotection mediated by sphingosine-1-phosphate and ganglioside GM-1 in wild-type and PKCε knockout mouse hearts

Cited by 147 publications

References 29 publications

Sphingolipid therapy in myocardial ischemia–reperfusion injury

Sphingolipid therapy in myocardial ischemia–reperfusion injury

Preservation of Base-line Hemodynamic Function and Loss of Inducible Cardioprotection in Adult Mice Lacking Protein Kinase Cϵ

Sphingosine 1-phosphate S1P₂ and S1P₃ receptor-mediated Akt activation protects against in vivo myocardial ischemia-reperfusion injury

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Cardioprotection mediated by sphingosine-1-phosphate and ganglioside GM-1 in wild-type and PKCε knockout mouse hearts

Cited by 147 publications

References 29 publications

Sphingolipid therapy in myocardial ischemia–reperfusion injury

Sphingolipid therapy in myocardial ischemia–reperfusion injury

Preservation of Base-line Hemodynamic Function and Loss of Inducible Cardioprotection in Adult Mice Lacking Protein Kinase Cϵ

Sphingosine 1-phosphate S1P2 and S1P3 receptor-mediated Akt activation protects against in vivo myocardial ischemia-reperfusion injury

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Sphingosine 1-phosphate S1P₂ and S1P₃ receptor-mediated Akt activation protects against in vivo myocardial ischemia-reperfusion injury