5893Adipose tissue secreted ceramides and related sphingolipids - potential modulators of vascular redox signalling in cardiovascular disease
5893Adipose tissue secreted ceramides and related sphingolipids - potential modulators of vascular redox signalling in cardiovascular disease
复制标题
5893脂肪组织分泌的神经酰胺和相关鞘脂——心血管疾病中血管氧化还原信号的潜在调节剂
DOI：
10.1093/eurheartj/ehz746.0085
复制
发表时间：
2019
影响因子：
39.3
通讯作者：
Akawi N
中科院分区：
文献类型：
--
作者：
Akawi N
研究背景脂肪组织（adipose tissue，AT）通过已知的脂肪因子和其他尚未鉴定的分泌分子在血管生物学调节中起着重要作用。近年来，基于组学的研究方法取得了新的进展，发现了更多的代谢产物，这些代谢产物是AT和血管系统之间的相互作用的驱动因素。目的本研究的主要目的是探讨AT分泌的神经酰胺对血管超氧阴离子（O2·−）的调节作用。方法对48例接受心脏手术的患者的成对胸壁和皮下AT的分泌组进行非靶向代谢分析，（心脏、血管和脂肪的牛津队列）沿着随后的鞘脂靶向定量使用液相色谱/质谱法进行。永生化的人主动脉内皮细胞（teloHAEC）与C6-神经酰胺（CerC 6）外源性处理20分钟和O2·−的生产使用光泽精增强chemilumination.ResultsMetabolomics差分（A）和富集分析（未显示）突出了两个脂肪库之间的鞘脂分泌水平的显着差异。从胸贮库产生和分泌更高量的神经酰胺，其中C16-神经酰胺（CerC 16）代表最丰富的差异分泌的神经酰胺（B）。与最低三分位数相比，胸部AT中神经酰胺的中间和最高三分位数与患者血管（即隐静脉（SV）和乳内动脉（IMA））中较高的O2·−生成显著相关（C）。用神经酰胺外源性处理teloHAEC增加了O2·−的产生和eNOS解偶联，在加入eNOS抑制剂L-NAME后，O2·−的负性增加。心脏病患者的AT分泌可能通过血管eNOS信号失调调节其血管氧化还原状态，导致内皮功能障碍。心血管疾病的标志。鸣谢/资助NovoNordisk基金会（NNF 15 CC 0018486）
BackgroundAdipose tissue (AT) plays a vital role in the modulation of vascular biology via known adipokines and other yet unidentified secreted molecules. Recent technological advances of omics-based approaches have enabled the identification of more metabolites that drive the currently recognised cross talk between the AT and the vasculature.PurposeThe main aim of this study is to explore the role of AT secreted ceramides on the regulation of vascular superoxide (O2·−) generation in cardiac patients.MethodsUntargeted metabolic profiling for the secretome of paired thoracic and subcutaneous ATs from 48 patients undergoing cardiac surgery (the Oxford cohort for heart, vessels and fat) along with the subsequent sphingolipids-targeted quantification were performed using liquid-chromatography/mass-spectrometry. Immortalized human aortic endothelial cells (teloHAEC) were treated exogenously with C6-ceramide (CerC6) for 20min and O2·− production was measured using lucigenin-enhanced chemiluminescence.ResultsMetabolomics differential (A) and enrichment analysis (not shown) highlighted the significant differences in sphingolipids secretion levels between the two fat depots. Higher amount of ceramides were produced and secreted from the thoracic depot with C16-ceramide (CerC16) representing the most abundant differentially secreted ceramide (B). Compared to the lowest tertile, the middle and highest tertiles of ceramides in thoracic AT were significantly associated with higher O2·− generation in patients' vessels namely saphenous veins (SV) and internal mammary arteries (IMA) (C). Exogenous treatment of teloHAEC with ceramide increased O2·− generation and eNOS uncoupling evidenced by more negative O2·− after addition of L-NAME, an inhibitor of eNOS (D).Results OverviewConclusionsIn this study, we demonstrate for the first time that sphingolipids, in particular ceramides, secreted from AT of cardiac patients may modulate their vascular redox state via dysregulating vascular eNOS signalling leading to endothelial dysfunction –a hallmark of cardiovascular disease.Acknowledgement/Fundingthe NovoNordisk Foundation (NNF15CC0018486)