血管内皮中神经酰胺的 "阴 "与 "阳"。

IF 7.4 1区 医学 Q1 HEMATOLOGY Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2024-08-01 Epub Date: 2024-06-20 DOI:10.1161/ATVBAHA.124.321158
Gopika SenthilKumar, Zachary Zirgibel, Katie E Cohen, Boran Katunaric, Alyssa M Jobe, Carolyn G Shult, Rachel H Limpert, Julie K Freed
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引用次数: 0

摘要

神经酰胺是一组具有生物活性的鞘磷脂,被称为新胆固醇,因为有强有力的证据表明,高血浆神经酰胺与内皮损伤、早期不良心血管事件风险和心血管代谢疾病的发展有关。这种关系引发了人们对抑制神经酰胺形成的治疗靶点的极大兴趣。然而,越来越多的数据挑战了神经酰胺只对心血管系统产生有害影响的模式。研究表明,神经酰胺是维持适当的内皮氧化还原状态、机械感觉和膜完整性所必需的。最近在临床前模型和离体人体微血管中进行的研究突出表明,神经酰胺形成的丧失实际上会导致血管内皮功能障碍。在此,我们将深入研究这些相互矛盾的发现,以评估神经酰胺是如何在血管内皮中同时发挥有益和有害作用的。我们提出了一个统一的理论,即虽然神经酰胺在生理刺激下的基础水平是产生 S1P(鞘磷脂-1-磷酸)等血管保护性代谢产物所必需的,但神经酰胺的长期积累会促进激活内皮细胞中的促氧化应激途径。在临床上,本文讨论的证据突显了通过治疗抑制神经酰胺的形成来降低心血管疾病风险的潜在挑战。
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Ying and Yang of Ceramide in the Vascular Endothelium.

Ceramides, a group of biologically active sphingolipids, have been described as the new cholesterol given strong evidence linking high plasma ceramide with endothelial damage, risk for early adverse cardiovascular events, and development of cardiometabolic disease. This relationship has sparked great interest in investigating therapeutic targets with the goal of suppressing ceramide formation. However, the growing data challenge this paradigm of ceramide as solely eliciting detrimental effects to the cardiovascular system. Studies show that ceramides are necessary for maintaining proper endothelial redox states, mechanosensation, and membrane integrity. Recent work in preclinical models and isolated human microvessels highlights that the loss of ceramide formation can in fact propagate vascular endothelial dysfunction. Here, we delve into these conflicting findings to evaluate how ceramide may be capable of exerting both beneficial and damaging effects within the vascular endothelium. We propose a unifying theory that while basal levels of ceramide in response to physiological stimuli are required for the production of vasoprotective metabolites such as S1P (sphingosine-1-phosphate), the chronic accumulation of ceramide can promote activation of pro-oxidative stress pathways in endothelial cells. Clinically, the evidence discussed here highlights the potential challenges associated with therapeutic suppression of ceramide formation as a means of reducing cardiovascular disease risk.

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来源期刊
CiteScore
15.60
自引率
2.30%
发文量
337
审稿时长
2-4 weeks
期刊介绍: The journal "Arteriosclerosis, Thrombosis, and Vascular Biology" (ATVB) is a scientific publication that focuses on the fields of vascular biology, atherosclerosis, and thrombosis. It is a peer-reviewed journal that publishes original research articles, reviews, and other scholarly content related to these areas. The journal is published by the American Heart Association (AHA) and the American Stroke Association (ASA). The journal was published bi-monthly until January 1992, after which it transitioned to a monthly publication schedule. The journal is aimed at a professional audience, including academic cardiologists, vascular biologists, physiologists, pharmacologists and hematologists.
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