Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide.
Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide.
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DOI：
10.1371/journal.pone.0021817
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Peters SL
中科院分区：
文献类型：
--
作者：
Spijkers LJ;van den Akker RF;Janssen BJ;Debets JJ;De Mey JG;Stroes ES;van den Born BJ;Wijesinghe DS;Chalfant CE;MacAleese L;Eijkel GB;Heeren RM;Alewijnse AE;Peters SL
高血压的特征之一是内皮功能障碍和血管重塑。由于鞘脂与血管收缩性和生长的调节有关，因此我们研究了鞘脂生物学是否在高血压中发生改变以及这是否反映在血管功能的改变中。在自发性高血压大鼠 (SHR) 和正常血压 Wistar-Kyoto (WKY) 大鼠的离体颈动脉中，通过给予鞘氨醇激酶抑制剂（二甲基鞘氨醇）或外源性应用鞘磷脂酶，将神经酰胺/S1P 比例转向神经酰胺主导，在 SHR 血管中诱导明显的内皮依赖性收缩（DMS：1.4±0.4 和 SMase： 2.1±0.1 mN/mm；n = 10)，在 WKY 血管中几乎不存在（DMS：0.0±0.0 和 SMase：0.6±0.1 mN/mm；n = 9，p<0.05）。成像质谱和免疫组织化学表明，这些收缩很可能是由神经酰胺介导的，并且依赖于 iPLA2、环氧合酶-1 和血栓素合酶。这些酶在 SHR 血管中的表达水平较高。同时，输注二甲基鞘氨醇导致麻醉的 SHR 血压显着升高（42±4%；n = 7），但在 WKY 中则不然（−12±10%；n = 6）。质谱脂质组学分析显示，与 WKY 相比，SHR 动脉组织中的神经酰胺水平升高（691±42 vs. 419±27 pmol，分别为 n = 3–5，p<0.05）。 SHR 鞘脂生物学的这些显着变化也反映在血浆神经酰胺水平升高（513±19 pmol WKY 与 645±25 pmol SHR，n = 6–12，p<0.05）。有趣的是，我们观察到原发性高血压患者血浆中的神经酰胺水平（与高血压分级相关）有类似的增加（185±8 pmol 与 252±23 pmol；n = 18 名正常血压患者与 n = 19 名高血压患者，p<0.05）。高血压与血管鞘脂生物学的显着改变有关，例如神经酰胺水平和信号传导升高，从而导致血管张力增加。
Hypertension is, amongst others, characterized by endothelial dysfunction and vascular remodeling. As sphingolipids have been implicated in both the regulation of vascular contractility and growth, we investigated whether sphingolipid biology is altered in hypertension and whether this is reflected in altered vascular function. In isolated carotid arteries from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats, shifting the ceramide/S1P ratio towards ceramide dominance by administration of a sphingosine kinase inhibitor (dimethylsphingosine) or exogenous application of sphingomyelinase, induced marked endothelium-dependent contractions in SHR vessels (DMS: 1.4±0.4 and SMase: 2.1±0.1 mN/mm; n = 10), that were virtually absent in WKY vessels (DMS: 0.0±0.0 and SMase: 0.6±0.1 mN/mm; n = 9, p<0.05). Imaging mass spectrometry and immunohistochemistry indicated that these contractions were most likely mediated by ceramide and dependent on iPLA2, cyclooxygenase-1 and thromboxane synthase. Expression levels of these enzymes were higher in SHR vessels. In concurrence, infusion of dimethylsphingosine caused a marked rise in blood pressure in anesthetized SHR (42±4%; n = 7), but not in WKY (−12±10%; n = 6). Lipidomics analysis by mass spectrometry, revealed elevated levels of ceramide in arterial tissue of SHR compared to WKY (691±42 vs. 419±27 pmol, n = 3–5 respectively, p<0.05). These pronounced alterations in SHR sphingolipid biology are also reflected in increased plasma ceramide levels (513±19 pmol WKY vs. 645±25 pmol SHR, n = 6–12, p<0.05). Interestingly, we observed similar increases in ceramide levels (correlating with hypertension grade) in plasma from humans with essential hypertension (185±8 pmol vs. 252±23 pmol; n = 18 normotensive vs. n = 19 hypertensive patients, p<0.05). Hypertension is associated with marked alterations in vascular sphingolipid biology such as elevated ceramide levels and signaling, that contribute to increased vascular tone.
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影响因子：
5
作者：
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