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Rewiring endothelial cell sphingolipid metabolism to favor S1P over ceramide signaling protects from coronary atherosclerosis

ABSTRACT: Growing evidence correlated changes in bioactive sphingolipids, particularly sphingosine-1-phosphate (S1P) and ceramides, with coronary artery diseases. Furthermore, specific plasma ceramide species can predict major cardiovascular events. Dysfunction of the endothelium lining lesion-prone areas plays a pivotal role in the initiation and progression of atherosclerosis. Yet, how sphingolipid metabolism and signaling change and contribute to endothelial dysfunction and atherosclerosis remain poorly understood. By using a mouse model of coronary atherosclerosis, we demonstrated that hemodynamic stress induces an early metabolic rewiring of endothelial sphingolipid de novo biosynthesis favoring S1P signaling over ceramide as protective response. Furthermore, our data are paradigm shift from the current believe that ceramide accrual contributes to endothelial dysfunction. The de novo biosynthesis of sphingolipids is commenced by serine palmitoyltransferase (SPT), and is downregulated by NOGO-B, an ER membrane protein. We showed that Nogo-B is upregulated by hemodynamic stress in myocardial endothelial cells (EC) of ApoE-/- mice and is expressed in the endothelium lining coronary lesions in mice and human. We demonstrated that mice lacking Nogo-B specifically in EC (Nogo-A/BECKOApoE-/-) were resistant to coronary atherosclerosis development and progression, and mortality. Fibrous cap thickness was significantly increased in Nogo-A/BECKOApoE-/- mice and correlated with reduced necrotic core and macrophage infiltration. Mechanistically, the deletion of Nogo-B in EC sustained the rewiring of sphingolipid metabolism towards S1P, imparting an atheroprotective transcriptional signature that refrain coronary atherogenesis and its progression. These findings also set forth the foundation for sphingolipid-based therapeutics to reduce the treat this condition.

ORGANISM(S): Mus musculus

PROVIDER: GSE254426 | GEO | 2024/02/12

REPOSITORIES: GEO

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Project description:Clinically significant radiation-induced lung injury (RILI) is associated with significant morbidity and mortality and a common toxicity in patients administered thoracic radiotherapy. While the molecular etiology of RILI is poorly understood, we previously characterized a murine model of RILI in which alterations in lung endothelial barrier integrity surfaced as a potentially important pathobiologic event. In these studies, inhibition of HMG-CoA reductase activity (simvastatin) reduced murine RILI-associated lung inflammation and vascular leak and attenuated radiation-induced dysregulation of sphingolipid metabolic pathway genes identified by genome-wide lung gene expression profiling. In the present study, we test the hypothesis that sphingolipid signaling components serve as important modulators of RILI pathobiology and novel therapeutic targets. Sphingolipid involvement in murine RILI was confirmed by radiation-induced increases in lung expression of sphingosine kinase (SphK) isoforms 1 and 2 and increases in the ratio of ceramide to cumulative sphingosine-1-phosphate (S1P) and dihydro-S1P (DHS1P) levels in plasma, bronchoalveolar lavage (BAL) fluid and lung tissue following 25 Gy exposure (6 weeks). Moreover, genetically-engineered mice with either targeted deletion of SphK1 (SphK1-/-), or with reduced expression of selective members of the S1P receptor family (S1PR1+/-, S1PR2-/-, S1PR3-/-,), exhibited marked susceptibility to RILI-mediated lung inflammation. Finally, we assessed the efficacy of three potent vascular barrier-protective S1P analogues FTY720 (FTY), fTysiponate (fTyS) and SEW-2871 (SEW) in attenuating indices of RILI. The phosphonate analogue, fTyS, and to a lesser degree SEW, exhibited significant attenuation of RILI and RILI-induced gene dysregulation compared to control RILI-challenged mice (6 weeks). In contrast, FTY failed to significantly alter physiologic or genomic changes compared to RILI-challenged controls. Together, these results support the targeting of sphingolipid components as a novel and effective therapeutic strategy in RILI. Four mice were treated with PBS as a control. Three mice were treated with (S)-FTY-phosphonate (0.1mg/kg) as a drug control. Three mice were treated with SEW-2871 (0.1mg/kg) as a drug control. Three mice were treated with FTY720 (0.1mg/kg) as a drug control. Three mice were treated with administered radiation (25 Gy) alone. Three mice were treated with both administered radiation (25 Gy) and (S)-FTY-phosphonate (0.1mg/kg). Three mice were treated with both administered radiation (25 Gy) and SEW-2871 (0.1mg/kg). Three mice were treated with both administered radiation (25 Gy) and FTY720 (0.1mg/kg).

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Rewiring endothelial cell sphingolipid metabolism to favor S1P over ceramide signaling protects from coronary atherosclerosis

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