Terry Christi M, Carlson Mary L, He Yuxia, Ulu Arzu, Morisseau Christophe, Blumenthal Donald K, Hammock Bruce D, Cheung Alfred K
Division of Nephrology and Hypertension, University of Utah, Utah, USA.
J Vasc Res. 2014;51(4):269-82. doi: 10.1159/000365251. Epub 2014 Sep 5.
Synthetic arteriovenous grafts (AVGs) used for hemodialysis frequently fail due to the development of neointimal hyperplasia (NH) at the vein-graft anastomosis. Inflammation and smooth-muscle cell (SMC) and myofibroblast proliferation and migration likely play an important role in the pathogenesis of NH. Epoxyeicosatrienoic acids (EETs), the products of the catabolism of arachidonic acid by cytochrome P450 enzymes, possess anti-inflammatory, antiproliferative, antimigratory and vasodilatory properties that should reduce NH. The degradation of vasculoprotective EETs is catalyzed by the enzyme, soluble epoxide hydrolase (sEH). sEH upregulation may thus contribute to NH development by the enhanced removal of vasculoprotective EETs. In this study, sEH, cytochrome P450 and EETs were examined after AVG placement in a porcine model to explore their potential roles in AVG stenosis. Increased sEH protein expression, decreased P450 epoxygenase activity and dysregulation of 5 oxylipin mediators were observed in the graft-venous anastomotic tissues when compared to control veins. Pharmacological inhibitors of sEH decreased the growth factor-induced migration of SMCs and fibroblasts, although they had no significant effect on the proliferation of these cells. These results provide insights on epoxide biology in vascular disorders and a rationale for the development of novel pharmacotherapeutic strategies to prevent AVG failure due to NH and stenosis.
用于血液透析的合成动静脉移植物（AVG）常常因静脉-移植物吻合处新内膜增生（NH）的发展而失效。炎症、平滑肌细胞（SMC）以及肌成纤维细胞的增殖和迁移可能在NH的发病机制中起重要作用。环氧二十碳三烯酸（EETs）是细胞色素P450酶催化花生四烯酸分解的产物，具有抗炎、抗增殖、抗迁移和血管舒张特性，应能减少NH。血管保护型EETs的降解由可溶性环氧化物水解酶（sEH）催化。因此，sEH上调可能通过增强对血管保护型EETs的清除而促进NH的发展。在本研究中，在猪模型中植入AVG后检测了sEH、细胞色素P450和EETs，以探讨它们在AVG狭窄中的潜在作用。与对照静脉相比，在移植物-静脉吻合组织中观察到sEH蛋白表达增加、P450环氧化酶活性降低以及5-氧脂素介质失调。sEH的药理抑制剂减少了生长因子诱导的SMC和成纤维细胞迁移，尽管它们对这些细胞的增殖没有显著影响。这些结果为血管疾病中的环氧化物生物学提供了见解，并为开发新的药物治疗策略以预防因NH和狭窄导致的AVG失效提供了理论依据。
