Elevating Endogenous Sphingosine-1-Phosphate (S1P) Levels Improves Endothelial Function and Ameliorates Atherosclerosis in Low Density Lipoprotein Receptor-Deficient (LDL-R−/−) Mice

Feuerborn, Renata; Besser, Manuela; Potì, Francesco; Burkhardt, Ralph; Weißen-Plenz, Gabriele; Ceglarek, Uta; Simoni, Manuela; Proia, Richard L.; Freise, Hendrik; Nofer, Jerzy–Roch

doi:10.1055/s-0038-1666870

Cited by 29 publications

(25 citation statements)

References 48 publications

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“…Obviously, there is an inconsistency whether iS1P acts dependent on S1P receptors or not. Moreover, a study using intravital microscopy in a murine atherosclerosis model revealed that iS1P reduced leukocyte adhesion to capillary wall and decreased LPS-induced endothelial permeability [61], thus corroborating our findings.…”

Section: Discussionsupporting

confidence: 89%

Downregulation of S1P Lyase Improves Barrier Function in Human Cerebral Microvascular Endothelial Cells Following an Inflammatory Challenge

Stepanovska

Lange

Schwalm

et al. 2020

IJMS

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Sphingosine 1-phosphate (S1P) is a key bioactive lipid that regulates a myriad of physiological and pathophysiological processes, including endothelial barrier function, vascular tone, vascular inflammation, and angiogenesis. Various S1P receptor subtypes have been suggested to be involved in the regulation of these processes, whereas the contribution of intracellular S1P (iS1P) through intracellular targets is little explored. In this study, we used the human cerebral microvascular endothelial cell line HCMEC/D3 to stably downregulate the S1P lyase (SPL-kd) and evaluate the consequences on endothelial barrier function and on the molecular factors that regulate barrier tightness under normal and inflammatory conditions. The results show that in SPL-kd cells, transendothelial electrical resistance, as a measure of barrier integrity, was regulated in a dual manner. SPL-kd cells had a delayed barrier build up, a shorter interval of a stable barrier, and, thereafter, a continuous breakdown. Contrariwise, a protection was seen from the rapid proinflammatory cytokine-mediated barrier breakdown. On the molecular level, SPL-kd caused an increased basal protein expression of the adherens junction molecules PECAM-1, VE-cadherin, and β-catenin, increased activity of the signaling kinases protein kinase C, AMP-dependent kinase, and p38-MAPK, but reduced protein expression of the transcription factor c-Jun. However, the only factors that were significantly reduced in TNFα/SPL-kd compared to TNFα/control cells, which could explain the observed protection, were VCAM-1, IL-6, MCP-1, and c-Jun. Furthermore, lipid profiling revealed that dihydro-S1P and S1P were strongly enhanced in TNFα-treated SPL-kd cells. In summary, our data suggest that SPL inhibition is a valid approach to dampenan inflammatory response and augmente barrier integrity during an inflammatory challenge.

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Section: Discussionsupporting

confidence: 89%

Downregulation of S1P Lyase Improves Barrier Function in Human Cerebral Microvascular Endothelial Cells Following an Inflammatory Challenge

Stepanovska

Lange

Schwalm

et al. 2020

IJMS

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“…Its circulating levels increase with obesity as well as upon fasting and correlate positively with markers of insulin resistance and inflammation (276,283,(346)(347)(348)(349)(350)(351). S1P directly acts on adipose tissue stromal cells to increase proliferation and decrease adipogenic differentiation, prompts adipocytes to increase inflammatory marker expression, triggers hepatocytes to increase inflammatory marker expression, survival, glucose uptake, and lipid accumulation, and leads to an overall decrease in insulin sensitivity (276,348,350,(352)(353)(354)(355)(356)(357)(358)(359)(360)(361). It also triggers skeletal muscle cells to increase glucose uptake, -cells to increase survival and glucosestimulated insulin secretion, vascular smooth muscle cells to increase tone, and endothelial cells to increase immune cell adhesion and permeability (276,348,350,(352)(353)(354)(355)(356)(357)(358)(359)(360)(361).…”

Section: Sphingolipidsmentioning

confidence: 99%

“…S1P directly acts on adipose tissue stromal cells to increase proliferation and decrease adipogenic differentiation, prompts adipocytes to increase inflammatory marker expression, triggers hepatocytes to increase inflammatory marker expression, survival, glucose uptake, and lipid accumulation, and leads to an overall decrease in insulin sensitivity (276,348,350,(352)(353)(354)(355)(356)(357)(358)(359)(360)(361). It also triggers skeletal muscle cells to increase glucose uptake, -cells to increase survival and glucosestimulated insulin secretion, vascular smooth muscle cells to increase tone, and endothelial cells to increase immune cell adhesion and permeability (276,348,350,(352)(353)(354)(355)(356)(357)(358)(359)(360)(361). SPHK1-deficient mice display decreased circulating S1P levels and are variably reported to exhibit either decreased WAT inflammation, liver inflammation and steatosis, and improved glucose tolerance and insulin resistance or increased -cell death and worsened glucose tolerance and insulin sensitivity (349,356,357,359).…”

Section: Sphingolipidsmentioning

confidence: 99%

Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication

Funcke

Scherer

2019

Journal of Lipid Research

227

165

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“…S1P signaling has emerged as an important regulator of cardiac and vascular homeostasis [10] and has reportedly been related to the pathogenesis of multiple cardiovascular outcomes, including coronary artery disease, atherosclerosis, myocardial infarction, and/or HF [11,[52][53][54][55][56][57][58][59][60][61][62][63]. In addition to the effects of S1P on atherosclerosis, which is regarded as a major mechanism involved in ischemic cardiovascular burden, a protective role of S1P on injured myocardium elicited by nonischemic causes has also been suggested [64][65][66].…”

Section: The Effect Of S1p On the Cellular Mechanisms Involved In Carmentioning

confidence: 99%

Novel Insights into the Role of HDL-Associated Sphingosine-1-Phosphate in Cardiometabolic Diseases

Diarte-Añazco

Méndez-Lara

Pérez

et al. 2019

IJMS

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Sphingolipids are key signaling molecules involved in the regulation of cell physiology. These species are found in tissues and in circulation. Although they only constitute a small fraction in lipid composition of circulating lipoproteins, their concentration in plasma and distribution among plasma lipoproteins appears distorted under adverse cardiometabolic conditions such as diabetes mellitus. Sphingosine-1-phosphate (S1P), one of their main representatives, is involved in regulating cardiomyocyte homeostasis in different models of experimental cardiomyopathy. Cardiomyopathy is a common complication of diabetes mellitus and represents a main risk factor for heart failure. Notably, plasma concentration of S1P, particularly high-density lipoprotein (HDL)-bound S1P, may be decreased in patients with diabetes mellitus, and hence, inversely related to cardiac alterations. Despite this, little attention has been given to the circulating levels of either total S1P or HDL-bound S1P as potential biomarkers of diabetic cardiomyopathy. Thus, this review will focus on the potential role of HDL-bound S1P as a circulating biomarker in the diagnosis of main cardiometabolic complications frequently associated with systemic metabolic syndromes with impaired insulin signaling. Given the bioactive nature of these molecules, we also evaluated its potential of HDL-bound S1P-raising strategies for the treatment of cardiometabolic disease.

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Elevating Endogenous Sphingosine-1-Phosphate (S1P) Levels Improves Endothelial Function and Ameliorates Atherosclerosis in Low Density Lipoprotein Receptor-Deficient (LDL-R−/−) Mice

Abstract: We conclude that raising endogenous S1P levels exerts anti-atherogenic effects in LDL-R mice that are mediated by favourable modulation of endothelial function.

Cited by 29 publications

References 48 publications

Downregulation of S1P Lyase Improves Barrier Function in Human Cerebral Microvascular Endothelial Cells Following an Inflammatory Challenge

Downregulation of S1P Lyase Improves Barrier Function in Human Cerebral Microvascular Endothelial Cells Following an Inflammatory Challenge

Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication

Novel Insights into the Role of HDL-Associated Sphingosine-1-Phosphate in Cardiometabolic Diseases

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