Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega-3 polyunsaturated fatty acids.
Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega-3 polyunsaturated fatty acids.
复制标题
DOI：
10.1016/j.taap.2012.09.007
复制
发表时间：
2012-11-01
影响因子：
3.8
通讯作者：
Walker, Mary K.
中科院分区：
文献类型：
--
作者：
Agbor, Larry N.;Walsh, Mary T.;Boberg, Jason R.;Walker, Mary K.
在体外，细胞色素P4501 A1（CYP 1A 1）代谢omega-3多不饱和脂肪酸（n-3 PUFA）、二十碳五烯酸（EPA）和二十二碳六烯酸（DHA），主要分别代谢为17，18-环氧二十碳四烯酸（17，18-EEQ）和19，20-环氧二十二碳五烯酸（19，20-EDP）。这些代谢物已被证明通过增加一氧化氮（NO）和激活钾通道介导血管舒张。我们假设CYP 1A 1的基因缺失会减少对n-3 PUFA的血管舒张反应，但不会减少代谢物，并因NO减少而增加血压（BP）。我们通过无线电遥测评估了CYP 1A 1野生型（WT）和敲除（KO）小鼠± NO合酶（NOS）抑制剂的血压。我们还评估了主动脉和肠系膜小动脉中乙酰胆碱（ACh）、EPA、DHA、17，18-EEQ和19，20-EDP的血管舒张作用。此外，我们评估了NO供体和DHA ±钾通道抑制剂的血管舒张作用。与WT相比，CYP 1A 1 KO小鼠是高血压的（平均BP，mmHg，WT 103±1，KO 116±1，n=5/基因型，p<0.05），并且表现出降低的心率（心跳/分钟，WT 575±5; KO 530±7; p<0.05）。然而，在CYP 1A 1 KO小鼠中，血压对NOS抑制的反应和对ACh和NO供体的血管舒张反应是正常的，这表明NO的生物利用度没有降低。相比之下，CYP 1A 1 KO小鼠在主动脉和肠系膜小动脉中对EPA和DHA的血管舒张反应显著减弱，但对CYP 1A 1代谢物17，18-EEQ和19，20-EDP的血管舒张反应正常，对钾通道抑制的反应正常。总之，这些数据表明，CYP 1A 1代谢n-3 PUFA在体内血管扩张剂和这些血管扩张剂的损失可能会导致血压升高。
In vitro cytochrome P4501A1 (CYP1A1) metabolizes omega-3 polyunsaturated fatty acids (n-3 PUFAs); eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), primarily to 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP), respectively. These metabolites have been shown to mediate vasodilation via increases in nitric oxide (NO) and activation of potassium channels. We hypothesized that genetic deletion of CYP1A1 would reduce vasodilatory responses to n-3 PUFAs, but not the metabolites, and increase blood pressure (BP) due to decreases in NO. We assessed BP by radiotelemetry in CYP1A1 wildtype (WT) and knockout (KO) mice ± NO synthase (NOS) inhibitor. We also assessed vasodilation to acetylcholine (ACh), EPA, DHA, 17,18-EEQ and 19,20-EDP in aorta and mesenteric arterioles. Further, we assessed vasodilation to an NO donor and to DHA ± inhibitors of potassium channels. CYP1A1 KO mice were hypertensive, compared to WT, (mean BP in mmHg, WT 103±1, KO 116±1, n=5/genotype, p<0.05), and exhibited a reduced heart rate (beats per minute, WT 575±5; KO 530±7; p<0.05). However, BP responses to NOS inhibition and vasorelaxation responses to ACh and an NO donor were normal in CYP1A1 KO mice, suggesting that NO bioavailability was not reduced. In contrast, CYP1A1 KO mice exhibited significantly attenuated vasorelaxation responses to EPA and DHA in both the aorta and mesenteric arterioles, but normal vasorelaxation responses to the CYP1A1 metabolites, 17,18-EEQ and 19,20-EDP, and normal responses to potassium channel inhibition. Taken together these data suggest that CYP1A1 metabolizes n-3 PUFAs to vasodilators in vivo and the loss of these vasodilators may lead to increases in BP.
登录
查看更多内容
影响因子：
8.3
作者：
Lund, Amie K.;Agbor, Larry N.;Walker, Mary K.
通讯作者：
Walker, Mary K.
影响因子：
10.8
作者：
Han, Zhiyi;Miwa, Yoshikazu;Sasaguri, Toshiyuki
通讯作者：
Sasaguri, Toshiyuki
DOI：
10.1073/pnas.190256997
发表时间：
2000-09-12
影响因子：
11.1
作者：
Lahvis, GP;Lindell, SL;Bradfield, CA
通讯作者：
Bradfield, CA
DOI：
10.1080/10623320490432434
发表时间：
2004-01-01
影响因子：
--
作者：
Eskin, SG;Turner, NA;McIntire, LV
通讯作者：
McIntire, LV
影响因子：
4.8
作者：
Boo, YC;Sorescu, G;Jo, HJ
通讯作者：
Jo, HJ