Department of Pathology and Laboratory Medicine, Cardiovascular Research Institute, Feil Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
Adv Exp Med Biol. 2022;1372:87-117. doi: 10.1007/978-981-19-0394-6_8.
The endothelium, inner layer of blood vessels, constitutes a metabolically active paracrine, endocrine, and autocrine organ, able to sense the neighboring environment and exert a variety of biological functions important to preserve the health of vasculature, tissues, and organs. Sphingolipids are both fundamental structural components of the eukaryotic membranes and signaling molecules regulating a variety of biological functions. Ceramide and sphingosine-1-phosphate (S1P), bioactive sphingolipids, have emerged as important regulators of cardiovascular functions in health and disease. In this review we discuss recent insights into the role of ceramide and S1P biosynthesis and signaling in regulating endothelial cell functions, in health and diseases. We also highlight advances into the mechanisms regulating serine palmitoyltransferase, the first and rate-limiting enzyme of de novo sphingolipid biosynthesis, with an emphasis on its inhibitors, ORMDL and NOGO-B. Understanding the molecular mechanisms regulating the sphingolipid de novo biosynthesis may provide the foundation for therapeutic modulation of this pathway in a variety of conditions, including cardiovascular diseases, associated with derangement of this pathway.
血管内皮细胞是血管的内层，构成了一个代谢活跃的旁分泌、内分泌和自分泌器官，能够感知周围环境，并发挥多种对维持血管、组织和器官健康至关重要的生物学功能。鞘脂类是真核细胞膜的基本结构成分，也是调节多种生物学功能的信号分子。神经酰胺和鞘氨醇-1-磷酸（S1P）是生物活性鞘脂类，它们已成为健康和疾病中调节心血管功能的重要调节剂。在这篇综述中，我们讨论了最近关于神经酰胺和 S1P 生物合成和信号转导在调节内皮细胞功能方面的作用的研究进展，包括在健康和疾病中的作用。我们还强调了调节从头合成鞘脂的限速酶丝氨酸棕榈酰转移酶的机制的进展，重点介绍了其抑制剂 ORMDL 和 NOGO-B。了解调节鞘脂从头生物合成的分子机制可能为在多种情况下（包括与该途径失调相关的心血管疾病）治疗性调节该途径提供基础。
