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.

项目概要/摘要 大动脉僵硬度在收缩期高血压的发生中起着因果作用。孤立 由于目前可用的抗药物治疗，收缩期高血压特别难以控制 高血压药物对收缩压和舒张压的影响相同，并且 舒张压随之降低至过低水平，导致 有症状的器官灌注不足，或收缩压降低不充分。 20- 羟基二十碳四酸 (20-HETE)，一种细胞色素 (CYP) 衍生的花生四烯酸 代谢产物，在高血压动物模型中升高，并与人类肥胖相关。 我们的初步数据表明，20-HETE 是一种不依赖于血管紧张素 II 的收缩压调节剂， 但不是高血压代谢综合征大鼠 (JCR) 的舒张压。大动脉 JCR 大鼠的僵硬度（收缩压的主要决定因素）也升高，并且 降低至 20-HETE 拮抗剂在正常 (Sprague-Dawley, SD) 大鼠中观察到的水平。 弹性蛋白降解是大动脉僵硬度的主要决定因素，在 JCR 大鼠中增加，并且 被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）。与 SD 大鼠相比，JCR 大鼠中 MMP12 的激活显着增加，并被 20- HETE拮抗剂。 20-HETE 和 MMP12 的来源负责增加弹性蛋白 退化和大动脉僵硬度尚不清楚。 JCR大鼠腹内脂肪切除术 将 MMP12 激活、弹性蛋白降解和大动脉僵硬度降低至 SD 中观察到的水平 大鼠，表明这种 20-HETE 和 MMP12 主要来源于内脏脂肪组织。 因此，我们假设代谢综合征中 20-HETE 升高会增加 MMP12 激活导致弹性蛋白降解增加、大动脉僵化和收缩压增加 血压。该假设将通过三个目标来解决：1）20-HETE 是否是 MMP12 激活、弹性蛋白降解、大动脉僵硬度和增加的主要决定因素 代谢综合征中的收缩压； 2) 是否依赖20-HETE的MMP12 激活是大动脉僵硬度和收缩压的主要决定因素 代谢综合征； 3）主要来源是动脉壁还是内脏脂肪组织 20-HETE 和 MMP12 负责增加大动脉硬度和收缩压 代谢综合征中的压力。这些研究的结果可能对管理很重要 孤立性收缩期高血压。