6β-hydroxytestosterone, a cytochrome P450 1B1 metabolite of testosterone, contributes to angiotensin II-induced hypertension and its pathogenesis in male mice.
6β-hydroxytestosterone, a cytochrome P450 1B1 metabolite of testosterone, contributes to angiotensin II-induced hypertension and its pathogenesis in male mice.
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6β-羟基睾酮，一种睾酮的细胞色素P450 1B1 代谢物，有助于血管紧张素II 诱导的高血压及其雄性小鼠的发病机制。
DOI：
10.1161/hypertensionaha.115.05396
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Malik,KafaitU
中科院分区：
文献类型：
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作者：
Pingili,AjeethK;Kara,Mehmet;Khan,NayaabS;Estes,AnneM;Lin,Zongtao;Li,Wei;Gonzalez,FrankJ;Malik,KafaitU
以前，我们发现Cyp 1b 1基因破坏减少了雄性小鼠血管紧张素II诱导的高血压和相关的病理生理变化。本研究旨在验证细胞色素P450 1B 1产生的睾酮代谢产物6β-羟基睾酮和16α-羟基睾酮参与血管紧张素II诱导的高血压及其发病机制的假设。在Cyp 1b 1 +/+小鼠中，血管紧张素II输注2周可增加心脏细胞色素P450 1B 1活性和血浆6β-羟基睾酮水平，但不改变Cyp 1b 1基因表达;在Cyp 1b 1 −/−小鼠中未观察到血管紧张素II的这些作用。血管紧张素II诱导的收缩压升高和相关的心脏肥大和纤维化（通过心内α-平滑肌肌动蛋白、胶原蛋白和转化生长因子-β的蓄积进行测量），以及烟酰胺腺嘌呤二核苷酸磷酸氧化酶活性和活性氧的产生增加;这些变化在Cyp 1b 1 −/−或去势Cyp 1b 1 +/+小鼠中最小化，并通过6β-羟基睾酮治疗恢复。在Cyp 1b 1 +/+小鼠中，6β-羟基睾酮没有改变血管紧张素II诱导的收缩压升高;在两种基因型中，基础收缩压也没有受到这种药物的影响。血管紧张素II或去势并没有改变Cyp 1b 1 +/+或Cyp 1b 1 −/−小鼠的心脏、血管紧张素II 1型受体、血管紧张素转换酶、Mas受体或雄激素受体mRNA水平。这些数据表明，睾酮代谢产物6β-羟基睾酮导致雄性小鼠血管紧张素II诱导的高血压和相关心脏发病机制，最可能是作为一种容许因子。此外，细胞色素P450 1B 1可以作为一个新的目标，开发药物治疗男性的肾素-血管紧张素和睾酮依赖性高血压和相关的发病机制。
Previously, we showed thatCyp1b1gene disruption minimizes angiotensin II–induced hypertension and associated pathophysiological changes in male mice. This study was conducted to test the hypothesis that cytochrome P450 1B1-generated metabolites of testosterone, 6β-hydroxytestosterone and 16α-hydroxytestosterone, contribute to angiotensin II–induced hypertension and its pathogenesis. Angiotensin II infusion for 2 weeks increased cardiac cytochrome P450 1B1 activity and plasma levels of 6β-hydroxytestosterone, but not 16α-hydroxytestosterone, inCyp1b1+/+mice without alteringCyp1b1gene expression; these effects of angiotensin II were not observed inCyp1b1−/−mice. Angiotensin II–induced increase in systolic blood pressure and associated cardiac hypertrophy, and fibrosis, measured by intracardiac accumulation of α-smooth muscle actin, collagen, and transforming growth factor-β, and increased nicotinamide adenine dinucleotide phosphate oxidase activity and production of reactive oxygen species; these changes were minimized inCyp1b1−/−or castratedCyp1b1+/+mice, and restored by treatment with 6β-hydroxytestoterone. InCyp1b1+/+mice, 6β-hydroxytestosterone did not alter the angiotensin II–induced increase in systolic blood pressure; the basal systolic blood pressure was also not affected by this agent in either genotype. Angiotensin II or castration did not alter cardiac, angiotensin II type 1 receptor, angiotensin-converting enzyme, Mas receptor, or androgen receptor mRNA levels inCyp1b1+/+or inCyp1b1−/−mice. These data suggest that the testosterone metabolite, 6β-hydroxytestosterone, contributes to angiotensin II–induced hypertension and associated cardiac pathogenesis in male mice, most probably by acting as a permissive factor. Moreover, cytochrome P450 1B1 could serve as a novel target for developing agents for treating renin–angiotensin and testosterone-dependent hypertension and associated pathogenesis in males.