Acetoacetate and β-hydroxybutyrate differentially regulate endothelin-1 and vascular endothelial growth factor in mouse brain microvascular endothelial cells
Acetoacetate and β-hydroxybutyrate differentially regulate endothelin-1 and vascular endothelial growth factor in mouse brain microvascular endothelial cells
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DOI：
10.1016/s1056-8727(99)00030-6
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发表时间：
1999-03-01
影响因子：
3
通讯作者：
Hoffman, WH
中科院分区：
文献类型：
--
作者：
Isales, CM;Min, L;Hoffman, WH
胰岛素依赖型糖尿病(IDDM)的特征是胰腺中的β细胞缺乏产生胰岛素的能力。这种胰岛素缺乏的代谢后果之一是肝脏酮体合成增加，导致严重的医学并发症，糖尿病酮症酸中毒(DKA)。而DKA又与脑水肿的发生有关。这种并发症的严重程度从死亡到亚临床表现，但似乎总是在某种程度上存在。脑水肿的病因尚不清楚，但渗透压、pH值的变化和胰岛素对血脑屏障的影响都被认为是可能的罪魁祸首。血脑屏障的不通透性是由血管内皮细胞(EC)维持的。因此，似乎EC功能的改变对于脑水肿的发展是必要的。然而，还没有研究检验酮小体对脑血管内皮细胞的影响。DKA中的两个主要酮体是乙酰乙酸酯(Acac)和β-羟基丁酸酯(BOHB)。在目前的研究中，我们研究了这些酮小体对一个主要的细胞内信号通路的影响。观察小鼠脑微血管内皮细胞(MBMEC)细胞内钙离子浓度的变化，以及两种血管活性多肽-内皮素-1(ET-1)和血管通透性因子(VPF/VEGF)的产生。目前的研究表明，BOHB可以增加血管通透性因子。相比之下，acac增加了强大的血管收缩因子--内皮素-1的产生。这一数据表明，脑内皮细胞是DKA代谢变化的潜在靶点。(C)1999年爱思唯尔科学公司。
Insulin-dependent diabetes mellitus (IDDM), is characterized by a lack of insulin production from beta cells in the pancreas. One of the metabolic consequences of this insulin deficit is an increased hepatic synthesis of ketone bodies, resulting in a serious medical complication, diabetic ketoacidosis (DKA). DKA, in turn, has been associated with the development of cerebral edema. The severity of this complication ranges from death to a subclinical presentation, but seems to be invariably present to some degree. The etiology of the cerebral edema is unknown, but changes in osmolality, pH, and insulin effects on the blood-brain barrier have all been suggested as possible culprits. Blood-brain barrier impermeability is maintained by the endothelial cells (EC) lining the blood vessels. Thus, it would seem likely that alterations in EC function would be necessary for the development of cerebral edema. However; no studies have examined the effects of ketone bodies on brain endothelial cells. The two major ketone bodies in DKA are acetoacetate (AcAc) and beta-hydroxybutyrate (BOHB). In the present study we examined the effect of these ketone bodies on a major intracellular signalling pathway. The changes in intracellular calcium concentration, and the production of two vasoactive peptides, endothelin-1 (ET-1) and vascular permeability factor (VPF/VEGF) in mouse brain microvascular endothelial cells (MBMEC). The present studies demonstrate the BOHB can increase vascular permeability factor. In contrast, AcAc increases the production of the potent vasoconstrictor, endothelin-1. This data would suggest that brain ECs are potential targets of the metabolic alterations in DKA. (C) 1999 Elsevier Science Inc.