Vascular cytochrome P450 4A expression and 20-hydroxyeicosatetraenoic acid synthesis contribute to endothelial dysfunction in androgen-induced hypertension
Vascular cytochrome P450 4A expression and 20-hydroxyeicosatetraenoic acid synthesis contribute to endothelial dysfunction in androgen-induced hypertension
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DOI：
10.1161/hypertensionaha.107.089599
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发表时间：
2007-07-01
期刊：
影响因子：
8.3
通讯作者：
Schwartzman, Michal Laniado
中科院分区：
文献类型：
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作者：
Singh, Harpreet;Cheng, Jennifer;Schwartzman, Michal Laniado
流行病学证据表明性别依赖性机制在高血压的病理生理学中起作用。已经表明，5 α-二氢睾酮（DHT）给药（56 mg/kg体重/天IP，持续14天）增加大鼠的血压、细胞色素P450 4A表达和20-羟基二十碳四烯酸合成。我们研究了血管20-羟基二十碳四烯酸合成增加是否是DHT处理的雄性Sprague-Dawley大鼠内皮功能障碍和高血压的基础，通过使用HET 0016，一种选择性细胞色素P450 4A抑制剂。HET 0016联合给药（10 mg/kg/天，IP给药14天）显著降低了DHT诱导的叶间动脉20-羟基二十碳四烯酸的产生（14.3 +/- 1.5 vs 1.5 +/- 0.5 ng/mg蛋白质/小时; P < 0.05）、超氧阴离子（246 +/- 47 vs. 31 +/- 8 cpm/μ g蛋白质）以及gp 91-phox、p47-phox和3-亚硝基化蛋白质的水平。此外，在苯肾上腺素预收缩的DHT处理大鼠的肾叶间动脉中，对乙酰胆碱的最大舒张反应（42.8 ± 4.8%）在存在HET 0016的情况下显著（P < 0.05）增加（81.5 ± 10.8%）。重要的是，HET 0016的给药消除了DHT诱导的高血压;收缩压从DHT治疗大鼠的146 +/- 2 mmHg降至130 +/- 1 mmHg（P < 0.05）。结果强烈暗示血管细胞色素P450 4A衍生的20-羟基二十碳四烯酸在雄激素诱导的内皮功能障碍和高血压的发展。
Epidemiological evidence suggests a role for sex-dependent mechanisms in the pathophysiology of hypertension. It has been shown that 5 alpha-dihydrotestosterone (DHT) administration (56 mg/kg of body weight per day IP for 14 days) increases blood pressure, cytochrome P450 4A expression, and 20-hydroxyeicosatetraenoic acid synthesis in rats. We examined whether increased vascular 20-hydroxyeicosatetraenoic acid synthesis underlies endothelial dysfunction and hypertension in DHT-treated male Sprague-Dawley rats by using HET0016, a selective cytochrome P450 4A inhibitor. Coadministration of HET0016 (10 mg/kg per day IP for 14 days) to DHT-treated rats markedly reduced DHT-induced interlobar arterial production of 20-hydroxyeicosatetraenoic acid (14.3 +/- 1.5 versus 1.5 +/- 0.5 ng/mg of protein per hour; P < 0.05), superoxide anion (246 +/- 47 versus 31 +/- 8 cpm/mu g of protein), and the levels of gp91-phox, p47-phox, and 3-nitrosylated proteins. Moreover, the maximal relaxing response to acetylcholine in phenylephrine-preconstricted renal interlobar arteries from DHT-treated rats (42.8 +/- 4.8%) significantly (P < 0.05) increased in the presence of HET0016 (81.5 +/- 10.8%). Importantly, the administration of HET0016 negated DHT-induced hypertension; systolic blood pressure was reduced from 146 +/- 2 mm Hg in DHT-treated rats to 130 +/- 1 mmHg (P < 0.05). The results strongly implicate vascular cytochrome P450 4A - derived 20-hydroxyeicosatetraenoic acid in the development of androgen-induced endothelial dysfunction and hypertension.