Sphingosine 1-phosphate signaling contributes to cardiac inflammation, dysfunction, and remodeling following myocardial infarction

Zhang, Fuyang; Xia, Yunlong; Yan, Wenjuan; Zhang, Haoqiang; Zhou, Fang; Zhao, Shengli; Wang, Wei; Zhu, Di; Xin, Chao; Lu, Yan; Zhang, Ling; He, Yuan; Gao, Erhe; Tao, Ling

doi:10.1152/ajpheart.00372.2015

Cited by 82 publications

(99 citation statements)

References 36 publications

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“…tive hypertrophy to maladaptive hypertrophy with clear evidence of cardiac fibrosis and dysfunction. 52,53 It has recently been shown that inhibition of SphK1/S1P signaling ameliorates infarction-induced cardiac remodeling and dysfunction, 54 and our finding of improvement in cardiac function after SphK1 inhibition without decreases in RVSP and RV hypertrophy might be attributable to a direct therapeutic benefit in maladaptive RV hypertrophy. Another factor is the short therapeutic window (3 weeks).…”

Section: Discussionsupporting

confidence: 54%

Sphingosine‐1‐Phosphate is Involved in the Occlusive Arteriopathy of Pulmonary Arterial Hypertension

et al. 2016

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Despite several advances in the pathobiology of pulmonary arterial hypertension (PAH), its pathogenesis is not completely understood. Current therapy improves symptoms but has disappointing effects on survival. Sphingosine-1-phosphate (S1P) is a lysophospholipid synthesized by sphingosine kinase 1 (SphK1) and SphK2. Considering the regulatory roles of S1P in several tissues leading to vasoconstriction, inflammation, proliferation, and fibrosis, we investigated whether S1P plays a role in the pathogenesis of PAH. To test this hypothesis, we used plasma samples and lung tissue from patients with idiopathic PAH (IPAH) and the Sugen5416/hypoxia/normoxia rat model of occlusive PAH. Our study revealed an increase in the plasma concentration of S1P in patients with IPAH and in early and late stages of PAH in rats. We observed increased expression of both SphK1 and SphK2 in the remodeled pulmonary arteries of patients with IPAH and PAH rats. Exogenous S1P stimulated the proliferation of cultured rat pulmonary arterial endothelial and smooth-muscle cells. We also found that 3 weeks of treatment of late-stage PAH rats with an SphK1 inhibitor reduced the increased plasma levels of S1P and the occlusive pulmonary arteriopathy. Although inhibition of SphK1 improved cardiac index and the total pulmonary artery resistance index, it did not reduce right ventricular systolic pressure or right ventricular hypertrophy. Our study supports that S1P is involved in the pathogenesis of occlusive arteriopathy in PAH and provides further evidence that S1P signaling may be a novel therapeutic target.Keywords: occlusive lesions, S1P, pulmonary, cardiac. Pulmonary arterial hypertension (PAH) remains debilitating and deadly despite advanced and expensive medical treatment. 1 Its pathogenic mechanisms have not been fully identified and therapeutically targeted. A limitation in the current treatment of patients with PAH is the inability of prostanoids, endothelin receptor blockers, phosphodiesterase inhibitors, or their various combinations to reverse the pulmonary arteriopathy. 2,3 An effective strategy in the development of more efficacious therapy would be to identify the molecular determinants of the arterial wall remodeling.Sphingosine-1-phosphate (S1P) is a biologically active lipid synthesized intracellularly by sphingosine kinase 1 (SphK1) and SphK2 and degraded by S1P lyase and various phosphatases. It is released by endothelial cells, red blood cells, activated platelets, and monocytes and has regulatory roles in several physiological and pathological processes. 4,5 Physiological levels of circulating S1P are vasculoprotective, whereas abnormal activation of SphK/S1P signaling is associated with diseases such as cancer, fibrosis, diabetes, and hypertension. [6][7][8][9][10] At high cellular or tissue levels, S1P is a proproliferative, antiapoptotic, promigratory, profibrotic, and proinflammatory signaling molecule. 11 SphK activity and S1P production are stimulated by numerous signals, including growth factors, cytokines, m...

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Section: Discussionsupporting

confidence: 54%

Sphingosine‐1‐Phosphate is Involved in the Occlusive Arteriopathy of Pulmonary Arterial Hypertension

et al. 2016

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“…This is associated with increased SphK1 and S1P 1 expression, suggesting that MI can regulate transcriptional activity of the genes encoding these proteins [52]. In this study administration of PF-543…”

Section: Sphk1 Inhibitors and Cardiac Hypertrophymentioning

confidence: 51%

“…FTY720 is converted to FTY720 phosphate, which is a S1P 1 functional antagonist (see [11] for review) and FTY720 is also a SphK1 inhibitor [8]. These authors also showed that SphK1/S1P/S1P 1 -dependent STAT3 signaling and inflammation was modulated by FTY720, thereby reducing post-MI cardiac remodeling and dysfunction [52]. Therefore, SphK1 might participate in the chronic pro-inflammatory and fibrotic responses during the hypertrophic process that eventually leads to cardiomyocyte apoptosis and RV failure.…”

Section: Sphk1 Inhibitors and Cardiac Hypertrophymentioning

confidence: 98%

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Sphingosine Kinase 1: A Potential Therapeutic Target in Pulmonary Arterial Hypertension?

Pyne

2017

Trends in Molecular Medicine

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This version is available at https://strathprints.strath.ac.uk/61649/ Strathprints is designed to allow users to access the research output of the University of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may not engage in further distribution of the material for any profitmaking activities or any commercial gain. You may freely distribute both the url (https://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to the Strathprints administrator: strathprints@strath.ac.ukThe Strathprints institutional repository (https://strathprints.strath.ac.uk) is a digital archive of University of Strathclyde research outputs. It has been developed to disseminate open access research outputs, expose data about those outputs, and enable the management and persistent access to Strathclyde's intellectual output. Abstract--Sphingosine kinase 1 (SphK1) knockout mice are protected against pulmonary hypertension and expression levels of the enzyme are increased in the lungs of pulmonary arterial hypertensive (PAH) patients. Moreover, sphingosine 1-phosphate can promote vascular remodeling/vasoconstriction in rodent and human pulmonary arterial smooth muscle cell models. Therefore, SphK1 might be a novel target for treatment of PAH.

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“…31 S1P binds to S1P receptor 1 and is thought to exert a cardioprotective effect through multiple pathways, including Akt signaling. 29 Although there is some controversy as to whether S1P/S1P receptor 1 signaling is cardioprotective, 32 the balance of evidence suggests that activation of S1P signaling may be a potential therapeutic target for HF.…”

Section: Cardiac Metabolismmentioning

confidence: 99%

Metabolomic Analysis in Heart Failure

Ikegami

Shimizu

Yoshida

et al. 2018

Circ J

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10 s, resulting in the cycling of approximately 6 kg of ATP daily, and the heart displays metabolic flexibility to meet this extremely high demand for energy. 8 Under normal conditions, more than 95% of the ATP consumed in the heart is generated by oxidative phosphorylation, while glycolysis is responsible for approximately 5% and the tricarboxylic acid (TCA) cycle for the remainder. Metabolism of fatty acids generates 70-90% of the ATP required by the heart, with the rest being produced by oxidation of glucose, lactate, ketone bodies, and amino acids. 9 It is well known that utilization of fatty acids is reduced in the failing heart and there is a metabolic shift to generation of ATP from glucose. Such metabolic remodeling is considered to be reasonable because HF is associated with hypoxia and ATP generation per oxygen atom is more efficient when glucose is consumed, compared with fatty acids. 9 In patients with advanced HF, the heart is unable to utilize either metabolite and thus "runs out of fuel". 10 It is reported that the ATP level is approximately 30% lower in failing human hearts compared with non-failing hearts. 11 In addition to this classical premise about the metabolic profile of the failing heart, recent advances in the field of metabolomics have indicated that several metabolites and/or metabolic pathways have a role in HF, as described next. LipidsUnder physiological conditions, the heart mainly generates ATP from fatty acids, but this process declines with progression of HF. Under left ventricular (LV) pressure overload, excessive lipolysis occurs in visceral fat because of increased adrenergic signaling, and this leads to high circulating levels of free fatty acids (FFAs). 12 The serum I t is thought that at least 6,500 low-molecular-weight metabolites exist in humans, and these metabolites have various important roles in biological systems in addition to proteins and genes. 1 Comprehensive assessment of endogenous metabolites is called metabolomics, and recent advances in this field have enabled us to understand the critical role of previously unknown metabolites or metabolic pathways in the maintenance of homeostasis under both physiological and stress conditions. Techniques of metabolomic analysis have been elegantly reported and reviewed elsewhere, 2-4 so the details will not be repeated here. Instead, we will describe the metabolites/metabolic pathways that have been characterized using these techniques and analyzed to improve understanding of various physiological and pathological processes in the field of cardiology. In particular, we will focus on heart failure (HF) and how metabolomic analysis has contributed for improving our understanding of the pathogenesis of this critical condition. Cardiac MetabolismThe number of patients with HF continues to increase and this condition has become a major healthcare issue in many countries. Because the prognosis of severe HF is poor, there are many unmet medical needs for these patients, 5, 6 The pathogenesis of HF is complex and a simple approa...

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Sphingosine 1-phosphate signaling contributes to cardiac inflammation, dysfunction, and remodeling following myocardial infarction

Cited by 82 publications

References 36 publications

Sphingosine‐1‐Phosphate is Involved in the Occlusive Arteriopathy of Pulmonary Arterial Hypertension

Sphingosine‐1‐Phosphate is Involved in the Occlusive Arteriopathy of Pulmonary Arterial Hypertension

Sphingosine Kinase 1: A Potential Therapeutic Target in Pulmonary Arterial Hypertension?

Metabolomic Analysis in Heart Failure

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