20-羟基二碳四烯酸在改变糖尿病血管反应性中的作用

M. H. M. Yousif, I. F. Benter, K. M. J. Dunn, A. J. Dahly-Vernon, S. Akhtar, R. J. Roman
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引用次数: 28

摘要

1本研究探讨了20-羟基二糖四烯酸(20-HETE)对链脲佐菌素(STZ)诱导的糖尿病大鼠血管功能的影响。2 . CYP4A蛋白的表达和20-HETE的形成在糖尿病动物的肾脏中升高,但在肾脏和肠系膜血管中没有升高。糖尿病大鼠离体肠系膜血管床和肾动脉段对去甲肾上腺素(NE)、内皮素-1 (ET-1)和血管紧张素II (Ang II)的血管收缩反应显著增强。用1-氨基苯并三唑(ABT, 50 mg kg−1 alt−1日)或n -羟基- n ' -(4-丁基-2-甲基苯基)甲脒(HET0016, 2.5 mg kg−1天−1)慢性治疗糖尿病大鼠,可减弱两种血管床对这些血管收缩剂的反应。3肾微粒体中20-HETE的合成减少了80%,证实ABT和HET0016的剂量足以实现系统阻断。体外添加HET0016 (1 μM)也能使糖尿病动物肾脏和肠系膜血管对NE的反应性增强,抑制20-HETE的形成90%,但对环氧化物的形成没有影响。糖尿病大鼠肠系膜血管对氨基酚和组胺的血管扩张反应降低,但肾动脉没有。用HET0016治疗糖尿病动物可改善两个血管床的血管扩张剂反应。与对照组相比,糖尿病动物肠系膜床血管对外源性20-HETE的敏感性升高。这些结果表明,20-HETE有助于糖尿病动物血管反应性的升高。这种影响不是由于CYP4A血管表达增加,而可能与CaMKII/Ras-GTPase系统增强激动剂诱导的底物(花生四烯酸)释放和/或血管对20-HETE的反应性升高有关。
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Role of 20-hydroxyeicosatetraenoic acid in altering vascular reactivity in diabetes

1 This study examined the role of 20-hydroxyeicosatetraenoic (20-HETE) in altering vascular function in streptozotocin (STZ)-induced diabetic rats.

2 The expression of CYP4A protein and the formation of 20-HETE were elevated in the kidney, but not in the renal or mesenteric vasculature, of diabetic animals. The vasoconstrictor responses to norepinephrine (NE), endothelin-1 (ET-1), and angiotensin II (Ang II) were significantly enhanced in the isolated perfused mesenteric vascular bed and renal artery segments of diabetic rats. Chronic treatment of the diabetic rats with 1-aminobenzotriazole (ABT, 50 mg kg−1 alt−1 diem) or N-hydroxy-N’-(4-butyl-2-methylphenyl) formamidine (HET0016, 2.5 mg kg−1 day−1) attenuated the responses to these vasoconstrictors in both vascular beds.

3 The synthesis of 20-HETE in renal microsomes was reduced by >80% confirming that the doses of ABT and HET0016 were sufficient to achieve system blockade. Addition of HET0016 (1 μM) in vitro also normalized the enhanced vascular responsiveness of renal and mesenteric vessels obtained from diabetic animals to NE and inhibited the formation of 20-HETE by >90% while having no effect on the formation of epoxides. Vasodilator responses to carbachol and histamine were reduced in the mesenteric vasculature, but not in renal arteries, of diabetic rats. Treatment of the diabetic animals with HET0016 improved vasodilator responses in both vascular beds. Vascular sensitivity to exogenous 20-HETE was elevated in the mesenteric bed of diabetic animals compared to controls.

4 These results suggest that 20-HETE contributes to the elevation in vascular reactivity in diabetic animals. This effect is not due to increased vascular expression of CYP4A but may be related to either enhanced agonist-induced release of substrate (arachidonic acid) by the CaMKII/Ras-GTPase system and/or elevated vascular responsiveness to 20-HETE.

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