20-HETE Increases Large Artery Stiffness and Systolic Blood Pressure in the Metabolic Syndrome

20-HETE 增加代谢综合征患者的大动脉僵硬度和收缩压

• 批准号: 9331983
• 负责人: Amanda Alexandra Soler
• 金额: $ 3.05万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9331983
• 关键词: Acids; Address; Adipose tissue; Adverse effects; Agonist; Alkane 1-monooxygenase; Angiotensin II; Animal Model; Animals; Antihypertensive Agents; Aorta; Arachidonic Acids; Blood Pressure; Blood Vessels; Body Weight; Carotid Arteries; Consequentialism; Cytochrome P450; Cytochrome a; Data; Development; Diastolic blood pressure; Elastin; Excision; Fatty acid glycerol esters; Human; Hydroxyeicosatetraenoic Acids; Hypertension; Incidence; Intra-abdominal; Isolated systolic hypertension; Lipectomy; MME gene; Measures; Mesenteric Arteries; Metabolic syndrome; Modeling; Myocardial Infarction; Obesity; Organ; Patients; Pharmacology; Play; Rattus; Regulation; Role; Source; Stroke; Tissues; United States; Visceral; arachidonate; arterial stiffness; hypoperfusion; inhibitor/antagonist; novel; receptor; systolic hypertension

Project Summary/Abstract Large artery stiffness plays a causal role in development of systolic hypertension. Isolated systolic hypertension is particularly difficult to manage due to currently available anti- hypertensive drugs' equal effect on both systolic and diastolic blood pressure, and consequential lowering of diastolic blood pressure to excessively low levels resulting in symptomatic organ hypoperfusion, or inadequate lowering of systolic blood pressure. 20- hydroxyeicosatetraeonic acid (20-HETE), a cytochrome (CYP)-derived arachidonic acid metabolite, is elevated in hypertensive animal models and associated with obesity in humans. Our preliminary data show that 20-HETE is an angiotensin II-independent regulator of systolic, but not diastolic blood pressure in hypertensive metabolic syndrome rats (JCR). Large artery stiffness, a major determinant of systolic blood pressure, was also elevated in JCR rats and decreased to that observed in normal (Sprague-Dawley, SD) rats by 20-HETE antagonists. Elastin degradation, a major determinant of large artery stiffness, was increased in JCR rats and reversed by 20-HETE antagonists. Elastin is the main substrate for matrix metalloproteinase 12 (MMP12). MMP12 activation was significantly increased in JCR vs. SD rats and inhibited by 20- HETE antagonists. The source(s) of 20-HETE and MMP12 responsible for increased elastin degradation and large artery stiffness are unknown. Intra-abdominal lipectomy in JCR rats decreased MMP12 activation, elastin degradation and large artery stiffness to levels seen in SD rats, suggesting that this 20-HETE and MMP12 are largely derived from visceral adipose tissue. Thus, we hypothesize that elevated 20-HETE in metabolic syndrome increases MMP12 activation leading to increased elastin degradation, large artery stiffness and increased systolic blood pressure. This hypothesis will be addressed in three aims: 1) Whether 20-HETE is a major determinant of MMP12 activation, elastin degradation, large artery stiffness and increased systolic blood pressure in metabolic syndrome; 2) Whether 20-HETE-dependent MMP12 activation is a major determinant of large artery stiffness and systolic blood pressure in metabolic syndrome; and 3) Whether arterial wall or visceral adipose tissue is the major source of 20-HETE and MMP12 responsible for increased large artery stiffness and systolic blood pressure in metabolic syndrome. Findings from these studies may be important for management of isolated systolic hypertension.

项目摘要/摘要 大动脉刚度在收缩压发育中起因果作用。孤立 由于目前可用的抗 - 高血压药物对收缩压和舒张压的同等作用，以及 舒张压的结果降低到过度低水平，导致 有症状的器官灌注或收缩压降低不足。 20- 羟基羟基苯二甲酸（20-HETE），一种细胞色素（CYP）衍生的花生四烯酸 代谢物在高血压动物模型中升高，与人类肥胖有关。 我们的初步数据表明，20-HETE是收缩期，无关的血管紧张素II独立的调节剂 但不是高血压代谢综合征大鼠（JCR）的舒张压。大动脉 刚度是收缩压的主要决定因素，在JCR大鼠和 降低到20位拮抗剂在正常（Sprague-Dawley，SD）大鼠中观察到的降低。 弹性蛋白降解是大动脉刚度的主要决定因素，在JCR大鼠和 由20-HETE拮抗剂逆转。弹性蛋白是基质金属蛋白酶12的主要底物 （MMP12）。 JCR与SD大鼠的MMP12激活显着增加，并被20-抑制 霍特对手。 20-HETE和MMP12的来源负责增加弹性蛋白 降解和大动脉刚度未知。 JCR大鼠的腹腔内脂肪切除术 MMP12激活，弹性降解和大动脉刚度降低到SD中的水平 大鼠表明这种20-HETE和MMP12主要源自内脏脂肪组织。 因此，我们假设代谢综合征的20-HETE升高会增加MMP12 激活导致弹性蛋白降解增加，大动脉刚度和收缩期增加 血压。该假设将以三个目的解决：1） MMP12激活，弹性蛋白降解，大动脉刚度的主要决定因素并增加 代谢综合征的收缩压； 2）是否依赖于20-Hete的MMP12 激活是大动脉刚度和收缩压的主要决定因素 代谢综合征； 3）动脉壁还是内脏脂肪组织是主要来源 20-HETE和MMP12负责增加大动脉刚度和收缩性血液 代谢综合征的压力。这些研究的发现对于管理可能很重要 分离的收缩压高血压。