Compensatory mechanism for homeostatic blood pressure regulation in Ephx2 gene-disrupted mice
Compensatory mechanism for homeostatic blood pressure regulation in Ephx2 gene-disrupted mice
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DOI：
10.1074/jbc.m608057200
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发表时间：
2007-02-02
影响因子：
4.8
通讯作者：
Hammock, Bruce D.
中科院分区：
文献类型：
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作者：
Luria, Ayala;Weldon, Steven M.;Hammock, Bruce D.
花生四烯酸衍生的环氧化物，环氧二十碳三烯酸，是血管稳态和炎症的重要调节剂，因此操纵它们的水平是一种潜在有用的药理学策略。可溶性环氧化物水解酶将环氧二十碳三烯酸转化为它们相应的二醇，二羟基二十碳三烯酸，从而修饰或消除这些氧脂的功能。为了更好地理解Ephx 2破坏的表型影响，比较了可溶性环氧化物水解酶缺失小鼠的两个独立衍生的集落。我们研究了这种基因型，评估蛋白质表达，生物流体氧脂素谱，组织氧脂素生产能力，和血压。Ephx 2基因破坏消除了来自每个菌落的肝、肾和心脏中的可溶性环氧化物水解酶蛋白表达和活性。血浆环氧脂肪酸水平增加，脂肪酸二醇水平降低，而脂氧合酶和环氧合酶依赖性氧化脂质的测量水平不变。肝和肾匀浆也显示出升高的环氧脂肪酸。然而，在全肾匀浆中，测量到20-羟基二十碳四烯酸形成增加4倍沿着脂氧合酶衍生的羟基化和前列腺素类产生增加3倍。然而，与之前的报道不同的是，Ephx 2空白集落均未显示基础血压的变化。最后，无可溶性环氧化物水解酶的小鼠在急性全身性炎症后显示出存活优势。数据表明，血压稳态可以通过增加Ephx 2缺失小鼠肾脏中血管收缩剂20-羟基二十碳四烯酸的产生来实现。肾代谢的这种转变可能是可溶性环氧化物水解酶基因丢失的代谢补偿。
Arachidonic acid-derived epoxides, epoxyeicosatrienoic acids, are important regulators of vascular homeostasis and inflammation, and therefore manipulation of their levels is a potentially useful pharmacological strategy. Soluble epoxide hydrolase converts epoxyeicosatrienoic acids to their corresponding diols, dihydroxyeicosatrienoic acids, modifying or eliminating the function of these oxylipins. To better understand the phenotypic impact of Ephx2 disruption, two independently derived colonies of soluble epoxide hydrolase-null mice were compared. We examined this genotype evaluating protein expression, biofluid oxylipin profile, tissue oxylipin production capacity, and blood pressure. Ephx2 gene disruption eliminated soluble epoxide hydrolase protein expression and activity in liver, kidney, and heart from each colony. Plasma levels of epoxy fatty acids were increased, and fatty acid diols levels were decreased, while measured levels of lipoxygenase-and cyclooxygenase-dependent oxylipins were unchanged. Liver and kidney homogenates also show elevated epoxide fatty acids. However, in whole kidney homogenate a 4-fold increase in the formation of 20-hydroxyeicosatetraenoic acid was measured along with a 3-fold increase in lipoxygenase-derived hydroxylation and prostanoid production. Unlike previous reports, however, neither Ephx2-null colony showed alterations in basal blood pressure. Finally, the soluble epoxide hydrolase-null mice show a survival advantage following acute systemic inflammation. The data suggest that blood pressure homeostasis may be achieved by increasing production of the vasoconstrictor, 20-hydroxyeicosatetraenoic acid in the kidney of the Ephx2-null mice. This shift in renal metabolism is likely a metabolic compensation for the loss of the soluble epoxide hydrolase gene.