Human CYP1A1, diet and dioxin-induced hypertension

人类 CYP1A1、饮食和二恶英诱发的高血压

• 批准号: 8366871
• 负责人: Mary K Walker
• 金额: $ 45.3万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8366871
• 关键词: Adult; American Heart Association; Animal Model; Aorta; Arachidonic Acids; Aromatic Hydrocarbons; Arteries; Blood Pressure; Blood Pressure Monitors; Blood Vessels; CYP1A1 gene; Cardiovascular Diseases; Cardiovascular system; Consumption; Contracts; Cyclooxygenase Inhibitors; Cytochromes; Data; Diet; Dietary Factors; Dioxins; Disease; Drug Delivery Systems; Eating; Environmental Pollutants; Equilibrium; Exhibits; Exposure to; Fatty Acids; Figs - dietary; Fish Oils; Fishes; Functional disorder; Gene Expression; Gene Proteins; Genes; Goals; Health; Hepatic; Human; Hypertension; Individual; Intake; Knockout Mice; Link; Lipoxygenase; Mediating; Mesentery; Morbidity - disease rate; Mus; Omega-3 Fatty Acids; Orthologous Gene; Outcome; Physiological; Polychlorinated Biphenyls; Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Research; Resistance; Testing; Tetrachlorodibenzodioxin; Thromboxanes; Time; Vascular Diseases; Vasoconstrictor Agents; Work; cardiovascular disorder risk; cardiovascular risk factor; cigarette smoking; dibenzo(1,4)dioxin; diphenyl; disorder risk; feeding; improved; in vivo; mortality; novel; pollutant; prevent; protein expression; receptor; response; risk benefit ratio; vasoconstriction

DESCRIPTION (provided by applicant): Considerable evidence demonstrates that dietary omega-3 polyunsaturated fatty acids (?-3 PUFAs) protect against cardiovascular morbidity and mortality. Although the American Heart Association recommends that all individuals consume ?-3 PUFAs from fish or fish oil supplements, many individuals avoid fish consumption due to concern about accumulated environmental pollutants. It is well known that halogenated aromatic hydrocarbon (HAH) pollutants bioaccumulate in fish and studies have linked human HAH exposure to an increased risk of cardiovascular disease. Exposure to HAHs highly induces cytochrome P4501A1 (CYP1A1) and notably, ?-3 PUFAs are the preferred endogenous fatty acid substrates for CYP1A1. Thus, sustained CYP1A1 induction could decrease ?-3 PUFAs, contributing to cardiovascular disease risk resulting from HAH exposure. Our research shows that exposure to a prototypical HAH, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces vascular dysfunction and hypertension in mice and these effects require induction of CYP1A1. Our preliminary data show that TCDD exposure of mice for 2 wks (prior to an increase in blood pressure) highly induces CYP1A1 in resistance arteries and depletes hepatic ?-3 PUFAs. This exposure also induces vascular gene expression consistent with ?-3 PUFA depletion and production of endothelial-derived contracting factors in CYP1A1 wildtype (WT), but not knockout (KO) mice. Further, TCDD increases arachidonic acid (AA)-mediated vasoconstriction and an ?-3 PUFA-enriched diet normalizes this effect. We hypothesize that CYP1A1 mediates TCDD-induced vascular dysfunction and hypertension via ?-3 PUFA depletion. We further hypothesize that human CYP1A1 will be as effective as mouse CYP1A1 in mediating these responses in vivo. To test this, in Aim 1 we will establish the requirement for CYP1A1 in TCDD-induced changes in vascular fatty acids and gene/protein expression, using CYP1A1 WT and KO mice, as well as mice where the mouse CYP1A1 and 1A2 genes have been replaced with the human CYP1A1/1A2 orthologs (hCYP1A). We will investigate the time course and magnitude of changes and the ability of ?-3 PUFAs to prevent them. The humanized CYP1A mouse will significantly improve our ability to extrapolate from mice to humans. In Aim 2 we will determine the mechanism by which CYP1A1 mediates TCDD-induced vascular dysfunction, using CYP1A1 WT and hCYP1A mice, and studying the aorta and mesenteric vasoreactivity ? and ?-3 PUFAs. In Aim 3 we will determine the ability of human CYP1A1 to mediate TCDD-induced hypertension and dietary ?-3 PUFAs to prevent it, using radiotelemetry. If proven correct these studies would provide the first experimental evidence that benefits of ?-3 PUFAs can offset vascular disease risk posed by HAH pollutants accumulated in fish. These outcomes also have broader human health implications. In particular, cigarette smoke has high levels of HAHs that induce CYP1A1 potentially contributing to vascular disease. Thus, CY?P1A1 inhibition could be a novel drug target for reducing vascular disease risk as a consequence of sustained CYP1A1 induction. PUBLIC HEALTH RELEVANCE: The American Heart Association recognizes that eating fish provides significant protection from developing cardiovascular disease and these benefits are derived from the intake of omega-3 polyunsaturated fatty acids; however, many individuals avoid fish consumption due to concern about accumulated environmental pollutants. While attempts have been made to estimate a risk-benefit ratio for fish consumption, no studies have experimentally investigated the interaction between dietary omega-3 polyunsaturated fatty acids, pollutants, and cardiovascular disease. The proposed studies will use an animal model to investigate the ability of dietary omega-3 polyunsaturated fatty acids to protect against pollutant induced vascular disease and hypertension, testing the premise that benefits of fish-derived fatty acids offset cardiovascular risk from pollutants accumulated in fish.

描述（由申请人提供）：大量证据表明，膳食ω-3多不饱和脂肪酸（？- 3 PUFA）预防心血管疾病发病率和死亡率。尽管美国心脏协会建议所有人都服用？3来自鱼或鱼油补充剂的PUFA，许多人由于担心累积的环境污染物而避免食用鱼。众所周知，卤代芳烃（HAH）污染物在鱼类中具有生物累积性，研究表明，人类接触HAH会增加患心血管疾病的风险。暴露于多环芳烃高度诱导细胞色素P4501 A1（CYP 1A 1），特别是，3 PUFA是CYP 1A 1的首选内源性脂肪酸底物。因此，持续的CYP 1A 1诱导可以降低？3 PUFA，导致HAH暴露导致的心血管疾病风险。我们的研究表明，暴露于典型的HAH，2，3，7，8-四氯二苯并对二恶英（TCDD），诱导血管功能障碍和高血压的小鼠，这些影响需要诱导CYP 1A 1。我们的初步数据表明，小鼠暴露于TCDD 2周（在血压升高之前）高度诱导阻力动脉中的CYP 1A 1，并消耗肝脏？3种PUFA。这种暴露也会诱导血管基因表达，这与？3在CYP 1A 1野生型（WT）而非敲除（KO）小鼠中，PUFA消耗和内皮源性收缩因子的产生。此外，TCDD增加花生四烯酸（AA）介导的血管收缩和？富含PUFA的饮食使这种影响正常化。我们推测CYP 1A 1通过？3 PUFA耗竭。我们进一步假设，人类CYP 1A 1将作为有效的小鼠CYP 1A 1在体内介导这些反应。为了测试这一点，在目标1中，我们将使用CYP 1A 1 WT和KO小鼠以及小鼠CYP 1A 1和1A 2基因已被人CYP 1A 1/1A 2直系同源物（hCYP 1A）取代的小鼠，确定TCDD诱导的血管脂肪酸和基因/蛋白质表达变化中对CYP 1A 1的需求。我们将调查变化的时间进程和幅度以及？三是预防为主。人源化CYP 1A小鼠将显著提高我们从小鼠外推到人类的能力。在目的2中，我们将确定CYP 1A 1介导TCDD诱导的血管功能障碍的机制，使用CYP 1A 1 WT和hCYP 1A小鼠，并研究主动脉和肠系膜血管反应性？然后呢？3种PUFA。在目标3中，我们将确定人类CYP 1A 1介导TCDD诱导的高血压和饮食的能力。3多不饱和脂肪酸，以防止它，使用无线电遥测。如果被证明是正确的，这些研究将提供第一个实验证据，证明？3多不饱和脂肪酸可以抵消鱼体内积累的高环芳烃污染物造成的血管疾病风险。这些结果还对人类健康产生了更广泛的影响。特别是，香烟烟雾具有高水平的HAH，其诱导CYP 1A 1，可能导致血管疾病。因此，CY？P1 A1抑制可能是一种新的药物靶点，用于降低持续CYP 1A 1诱导导致的血管疾病风险。 公共卫生相关性：美国心脏协会认识到，吃鱼可以显著防止心血管疾病的发生，这些益处来自于摄入omega-3多不饱和脂肪酸;然而，许多人由于担心累积的环境污染物而避免食用鱼类。虽然已经尝试估计食用鱼类的风险-效益比，但没有研究通过实验研究了膳食ω-3多不饱和脂肪酸，污染物和心血管疾病之间的相互作用。拟议中的研究将使用动物模型来研究膳食omega-3多不饱和脂肪酸对污染物的保护能力 研究人员还对鱼类衍生脂肪酸的益处抵消了鱼类中积累的污染物造成的心血管风险这一前提进行了测试。

项目成果

Dietary Omega-3 Polyunsaturated Fatty Acids Prevent Vascular Dysfunction and Attenuate Cytochrome P4501A1 Expression by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin.

膳食 Omega-3 多不饱和脂肪酸可预防血管功能障碍并通过 2,3,7,8-四氯二苯并-P-二恶英减弱细胞色素 P4501A1 表达。

• DOI: 10.1093/toxsci/kfw145
• 发表时间: 2016
• 期刊: Toxicological sciences : an official journal of the Society of Toxicology
• 作者: Wiest,ElaniF;Walsh-Wilcox,MaryT;Rothe,Michael;Schunck,Wolf-Hagen;Walker,MaryK
• 通讯作者: Walker,MaryK