Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure.
Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure.
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DOI：
10.1038/nm.3934
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发表时间：
2015-09
期刊：
影响因子：
82.9
通讯作者：
Di Lorenzo A
中科院分区：
文献类型：
--
作者：
Cantalupo A;Zhang Y;Kothiya M;Galvani S;Obinata H;Bucci M;Giordano FJ;Jiang XC;Hla T;Di Lorenzo A
内皮功能障碍是包括高血压在内的许多心血管疾病的关键因素。尽管脂质信号与内皮功能障碍和心血管疾病有关，但具体的分子机制尚不清楚。在这里，我们报道了内质网的膜蛋白Nogo-B，调节内皮鞘脂的生物合成，直接影响血管功能和血压。Nogo-B抑制丝氨酸棕榈酰基转移酶，丝氨酸棕榈酰基转移酶是新生鞘脂生物合成途径的限速酶，从而控制内皮鞘磷脂1-磷酸和自分泌的产生，G蛋白偶联受体依赖于该代谢物的信号传导。内皮细胞系统性或特异性缺乏Nogo-B的小鼠具有低血压，对血管紧张素ii诱导的高血压具有抗性，并保留了内皮功能和一氧化氮释放。在缺乏Nogo-B的小鼠中，肉豆蔻素对丝氨酸棕榈酰转移酶的药理学抑制可恢复内皮功能障碍和血管紧张素ii诱导的高血压。我们的研究发现Nogo-B是局部鞘脂合成的关键抑制剂，并表明内皮内的自分泌鞘脂信号传导对血管功能和血压稳态至关重要。
Endothelial dysfunction is a critical factor in many cardiovascular diseases, including hypertension. Although lipid signaling has been implicated in endothelial dysfunction and cardiovascular disease, specific molecular mechanisms are poorly understood. Here we report that Nogo-B, a membrane protein of the endoplasmic reticulum, regulates endothelial sphingolipid biosynthesis with direct effects on vascular function and blood pressure. Nogo-B inhibits serine palmitoyltransferase, the rate-limiting enzyme of the de novo sphingolipid biosynthetic pathway, thereby controlling production of endothelial sphingosine 1-phosphate and autocrine, G protein–coupled receptor–dependent signaling by this metabolite. Mice lacking Nogo-B either systemically or specifically in endothelial cells are hypotensive, resistant to angiotensin II–induced hypertension and have preserved endothelial function and nitric oxide release. In mice that lack Nogo-B, pharmacological inhibition of serine palmitoyltransferase with myriocin reinstates endothelial dysfunction and angiotensin II–induced hypertension. Our study identifies Nogo-B as a key inhibitor of local sphingolipid synthesis and shows that autocrine sphingolipid signaling within the endothelium is critical for vascular function and blood pressure homeostasis.