Suppression of endothelial ceramide de novo biosynthesis contributes to cardiometabolic diseases
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PROVIDER: PRJNA1167768 | ENA |
REPOSITORIES: ENA
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Project description:Metabolic disorders and obesity increase the risk for cardiovascular (CV) disease, including hypertension, atherosclerosis, and myocardial infarction. Systemic endothelial dysfunction, a well-established response to CV risk factors, precedes the development of CV diseases. However, growing evidence suggest that endothelial dysregulation also contributes to metabolic disorders, underlying a centric role of the endothelium in cardiometabolic diseases. The accrual of the sphingolipid ceramide, bioactive molecule, has been causally implicated in endothelial dysfunction in vitro. However, direct in vivo evidence supporting the accrual of ceramide in the endothelium, underlying mechanisms, and pathological implications are lacking. Here, we showed that the suppression rather than the accrual of ceramides is causally linked to endothelial dysfunction, and imparts a pro-inflammatory and pro-atherosclerotic phenotype, contributing to both vascular and metabolic disorders. Mechanistically, the upregulation of Nogo-B and ORMDLs proteins, inhibitors of the first and rate limiting enzyme of the de novo biosynthesis, in the endothelium of obese and diabetic mice suppresses sphingolipid signaling, particularly ceramides and sphingosine-1-phosphate, resulting in vascular and metabolic dysfunctions. Systemic and endothelial specific deletion of Nogo-B restores sphingolipid signaling and functions of the endothelium, improves hypertension and lowers hepatic glucose production. Our results demonstrating that Nogo-B-mediated suppression of sphingolipid metabolism and signaling in the endothelium has pathological implication in cardiometabolic disorders and set a framework for the development of therapeutic strategies to treat these conditions.
2025-01-24 | GSE278555 | GEO
Project description:The bioactive sphingolipid ceramide, generated by ceramide synthase, is an adaptive stress effector induced in response to various stress stimuli such as aging. In fact, ceramide synthase (CerS) was first discovered in yeast as a longevity assurance gene (LAG1), as the reduced ceramide generation consequent to LAG1 deletion increased longevity. There are six homologues of mammalian LAG1/ceramide synthases (CerS1-6) that generate ceramides with different fatty acid chain lengths with distinct functions and hydrophobicity. Ceramide can be metabolized by sphingosine kinase 1 or 2 for the generation of pro-survival sphingosine 1-phosphate (S1P), which enhances immune cell egress to the blood stream, activating immune function. Ceramide is known to induce mitophagy and cell death. Here we investigated the role of this sphingolipid pathway in immune function, specifically T cell functions, via high throughput expression profiling.
2021-01-01 | GSE148498 | GEO
Project description:BackgroundWe previously showed that cardiomyocyte Krϋppel-like factor (KLF) 5 regulates cardiac fatty acid oxidation. As heart failure has been associated with altered fatty acid oxidation, we investigated the role of cardiomyocyte KLF5 in lipid metabolism and pathophysiology of ischemic heart failure.MethodsUsing real-time polymerase chain reaction and Western blot, we investigated the KLF5 expression changes in a myocardial infarction (MI) mouse model and heart tissue from patients with ischemic heart failure. Using 2D echocardiography, we evaluated the effect of KLF5 inhibition after MI using pharmacological KLF5 inhibitor ML264 and mice with cardiomyocyte-specific KLF5 deletion (αMHC [α-myosin heavy chain]-KLF5-/-). We identified the involvement of KLF5 in regulating lipid metabolism and ceramide accumulation after MI using liquid chromatography-tandem mass spectrometry, and Western blot and real-time polymerase chain reaction analysis of ceramide metabolism-related genes. We lastly evaluated the effect of cardiomyocyte-specific KLF5 overexpression (αMHC-rtTA [reverse tetracycline-controlled transactivator]-KLF5) on cardiac function and ceramide metabolism, and rescued the phenotype using myriocin to inhibit ceramide biosynthesis.ResultsKLF5 mRNA and protein levels were higher in human ischemic heart failure samples and in rodent models at 24 hours, 2 weeks, and 4 weeks post-permanent left coronary artery ligation. αMHC-KLF5-/- mice and mice treated with ML264 had higher ejection fraction and lower ventricular volume and heart weight after MI. Lipidomic analysis showed that αMHC-KLF5-/- mice with MI had lower myocardial ceramide levels compared with littermate control mice with MI, although basal ceramide content of αMHC-KLF5-/- mice was not different in control mice. KLF5 ablation suppressed the expression of SPTLC1 and SPTLC2 (serine palmitoyltransferase [SPT] long-chain base subunit ()1 2, respectively), which regulate de novo ceramide biosynthesis. We confirmed our previous findings that myocardial SPTLC1 and SPTLC2 levels are increased in heart failure patients. Consistently, αMHC-rtTA-KLF5 mice showed increased SPTLC1 and SPTLC2 expression, higher myocardial ceramide levels, and systolic dysfunction beginning 2 weeks after KLF5 induction. Treatment of αMHC-rtTA-KLF5 mice with myriocin that inhibits SPT, suppressed myocardial ceramide levels and alleviated systolic dysfunction.ConclusionsKLF5 is induced during the development of ischemic heart failure in humans and mice and stimulates ceramide biosynthesis. Genetic or pharmacological inhibition of KLF5 in mice with MI prevents ceramide accumulation, alleviates eccentric remodeling, and increases ejection fraction. Thus, KLF5 emerges as a novel therapeutic target for the treatment of ischemic heart failure.
| S-EPMC7965352 | biostudies-literature
Project description:Analysis of Neuroblastoma SH-SY5Y cell line treated with C2 ceramide, or combination of C2 ceramide and PJ34. Samples were collected in three time points: 3 hours, 6 hours and 24 hours. Results provide insight into the mechanism of cramide induced cell death and role of poly (ADP-ribose) polymerase in these proces.
2016-11-29 | GSE90587 | GEO
Project description:Methamphetamine is a highly addictive psychostimulant that causes profound damage to the brain and other body organs. Post mortem studies of human tissues have linked the use of this drug to diseases associated with aging, such as coronary atherosclerosis and pulmonary fibrosis, but the molecular mechanism underlying these findings remains unknown. Here we used functional lipidomics and transcriptomics experiments to study abnormalities in lipid metabolism in select regions of the brain and, to a greater extent, peripheral organs and tissues of rats that self-administered methamphetamine. Experiments in various cellular models (primary mouse fibroblasts and myotubes) allowed us to investigate the molecular mechanisms of systemic inflammation and cellular aging related to methamphetamine abuse. We report now that methamphetamine accelerates cellular senescence and activates transcription of genes involved in cell-cycle control and inflammation by stimulating production of the sphingolipid messenger ceramide. This pathogenic cascade is triggered by reactive oxygen species, likely generated through methamphetamine metabolism via cytochrome P450, and involves the recruitment of nuclear factor-?B (NF-?B) to induce expression of enzymes in the de novo pathway of ceramide biosynthesis. Inhibitors of NF-?B signaling and ceramide formation prevent methamphetamine-induced senescence and systemic inflammation in rats self-administering the drug, attenuating their health deterioration. The results suggest new therapeutic strategies to reduce the adverse consequences of methamphetamine abuse and improve effectiveness of abstinence treatments.
| S-EPMC4324822 | biostudies-literature
Project description:Hematopoietic stem and progenitor cells (HSPCs) rely upon cellular crosstalk, including extracellular vesicles (EVs) for lifelong niche occupancy and cellular function. Vesicle secretion is tightly linked to intracellular homeostasis; however, these mechanisms are poorly understood in HSPCs, particularly at the single-cell level. In this study, we target ceramide-dependent EV secretion by pharmacologic blockade in ex vivo expanded HSPCs. We use these cells to investigate single-cell resolution of short-term and delayed transcriptional changes induced by ceramide-EV inhibition.
2023-10-01 | GSE226348 | GEO
Project description:We have used human umbilical vein endothelial cell line (HUVEC) as a model to investigate the effect of ultrasound (US) activated micro-bubbles on sensitizing the tumour response to radiation and to check the implication of this approach on gene expression. The use of micro-bubbles in cancer therapy is a novel approach that is being recently investigated, and patterns of gene expressions were not yet characterized. Gene analysis has identified about 19,264 genes; where, 239 – 517 genes have shown more than two folds up-regulation in response to the different treatments. This included a number of genes that are known to be involved in apoptosis and ceramide-induced apoptosis pathways, such as Sphingomyelin phosphodiesterase 2, neutral sphingomyelinase (SMPD2), sphingomyelin phosphodiesterase 1, acid lysosomal (ASM; SMPD1), UDP-galactose ceramide galactosyltransferase (UGT8), cytochrome c oxidase (COX6B1), Caspase-9 and mitogen-activated protein kinase kinase 1 (MAP2K1). To verify these results, we have performed Real time RT-PCR, which indicated an up-regulation that ranged from 2 to 200 folds, specifically in the combined treatment of US, 3.3% micro-bubbles and 8 Gy. The observed higher levels of expression of UGT8, SMPD2 and Caspase 9-alpha when compared to the control or to radiation only indicated the involvement of ceramide, which possibly induces apoptosis . These results support the hypothesis that micro-bubbles play a role in increasing sensitization to radiation, and can prove to be an effective cancer therapeutic approach. Gene analysis has identified about 19,264 genes; where, 239 – 517 genes have shown more than two folds up-regulation in response to the different treatments. This included a number of genes that are known to be involved in apoptosis and ceramide-induced apoptosis pathways, such as Sphingomyelin phosphodiesterase 2, neutral sphingomyelinase (SMPD2), sphingomyelin phosphodiesterase 1, acid lysosomal (ASM; SMPD1), UDP-galactose ceramide galactosyltransferase (UGT8), cytochrome c oxidase (COX6B1), Caspase-9 and mitogen-activated protein kinase kinase 1 (MAP2K1). To verify these results, we have performed Real time RT-PCR, which indicated an up-regulation that ranged from 2 to 200 folds, specifically in the combined treatment of US, 3.3% micro-bubbles and 8 Gy. The observed higher levels of expression of UGT8, SMPD2 and Caspase 9-alpha when compared to the control or to radiation only indicated the involvement of ceramide, which possibly induces apoptosis . These results support the hypothesis that micro-bubbles play a role in increasing sensitization to radiation, and can prove to be an effective cancer therapeutic approach.
2009-08-27 | E-GEOD-17525 | biostudies-arrayexpress
Project description:Ceramide is an important lipid in skin barrier function. Psoriasis is a chronic inflammatory skin disease, and the skin barrier function has disturbed. Furthermore, the balance of each ceramide species in stratum corneum is disrupted in psoriatic skin. However, it involved remains unclear what detailed mechanism ceramide species changed in psoriatic skin lesion. We comprehensively investigated lipid metabolism including ceramide in skin of psoriasis patients by DNA microarray analysis. The expression level of PNPLA1 gene involved in acylceramide synthesis which is epidermis-specific ceramide species essential for skin barrier function was decreased in psoriatic skin. In contrast, the expression level of lipid metabolism-related enzymes gene including ceramide were increased in psoriatic skin. Consequently, the acylceramide synthesis was decreased in skin of psoriasis patients, suggesting that increased biosynthesis of other sphingolipids to supplement the function of acylceramide may cause the pathology of psoriasis.
2024-03-16 | GSE168640 | GEO
Project description:Matrix metalloproteinase 12 (MMP12) is a macrophage-secreted protein that is massively upregulated as a pro-inflammatory factor in metabolic and vascular tissues of mice and humans suffering from cardiometabolic diseases (CMDs). However, the molecular mechanisms explaining the contributions of MMP12 to CMDs are still unclear.
2023-12-05 | PXD046532 | Pride
Project description:Aging stress and ceramide dependent RNA sequencing expression profiling depends on ceramide synthase 6
| PRJNA624654 | ENA