Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension
Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension
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DOI：
10.1073/pnas.081627898
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发表时间：
2001-04-24
影响因子：
11.1
通讯作者：
Capdevila, JH
中科院分区：
文献类型：
--
作者：
Holla, VR;Adas, F;Capdevila, JH
高血压是心血管、大脑和肾脏疾病发病率和死亡率的主要原因。在这里，我们展示了Cyp 4a14基因的破坏导致高血压，像大多数人类高血压一样，在男性中更为严重。雄性Cyp 4a14（-/-）小鼠血浆雄激素、肾脏Cyp 4a12表达增加。并形成高血压的20-羟基四烯酸酯。去势使Cyp 4a14（-/-）小鼠的血压正常化，并使Cyp 4a12表达和花生四烯酸-羟基化最小化，雄激素替代恢复高血压表型、Cyp 4a12表达和20-羟基花生四烯酸形成。我们得出结论，雄激素介导的Cyp 4a花生四烯酸单加氧酶的调节是控制全身血压的肾脏机制的重要组成部分。这些结果为Cyp 4a亚型在心血管生理学中的作用提供了直接证据。建立Cyp 4a14（-/-）小鼠作为单基因模型，研究血压、性激素和P450 ω -羟化酶之间的因果关系，并建议人类Cyp 4A同源物作为分析人类高血压遗传和分子基础的候选基因。
Hypertension is a leading cause of cardiovascular, cerebral, and renal disease morbidity and mortality. Here we show that disruption of the Cyp 4a14 gene causes hypertension, which is, like most human hypertension, more severe in males. Male Cyp 4a14 (-/-) mice show increases in plasma androgens, kidney Cyp 4a12 expression. and the formation of prohypertensive 20-hydroxyarachidonate. Castration normalizes the blood pressure of Cyp 4a14 (-/-) mice and minimizes Cyp 4a12 expression and arachidonate omega -hydroxylation, Androgen replacement restores hypertensive phenotype, Cyp 4a12 expression, and 20-hydroxy-arachidonate formation. We conclude that the androgen-mediated regulation of Cyp 4a arachidonate monooxygenases is an important component of the renal mechanisms that control systemic blood pressures. These results provide direct evidence for a role of Cyp 4a isoforms in cardiovascular physiology. establish Cyp 4a14 (-/-) mice as a monogenic: model for the study of cause/effect relationships between blood pressure, sex hormones, and P450 omega -hydroxylases, and suggest the human CYP 4A homologues as candidate genes for the analysis of the genetic and molecular basis of human hypertension.