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 大动脉僵硬在收缩期高血压的发生中起着因果作用。孤立 由于目前可用的抗高血压药物，收缩期高血压尤其难以管理。 高血压药物对收缩压和舒张压的同等作用 随之而来的舒张压降低到过低水平，导致 有症状的器官灌流不足，或收缩压降低不足。20- 20-羟基二十碳四烯酸(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，并与人类肥胖有关。 我们的初步数据显示，20-HETE是一种血管紧张素II非依赖性收缩压调节因子， 但不包括高血压代谢综合征大鼠(JCR)的舒张压。大动脉 僵硬是收缩压的主要决定因素，在JCR大鼠和 20-HETE拮抗剂降低至正常(SD，SD)大鼠的水平。 弹性蛋白降解是大动脉僵硬的主要决定因素，在JCR大鼠和 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)。JCR大鼠与SD大鼠比较，MMP12活性显著升高，而20-羟色胺抑制其活性。 他有敌手。20-HETE和MMP12的来源(S)导致弹性蛋白增加 退化和大动脉僵硬是未知的。JCR大鼠腹内脂肪切除术的实验研究 降低MMP12活性、弹性蛋白降解和大动脉僵硬，达到SD患者的水平 提示这种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患者20-HETE升高会增加MMP12 激活导致弹性蛋白降解增加、大动脉僵硬和收缩压增加 血压。这一假设将在三个目标中得到解决：1)20-HETE是否是一种 MMP12激活、弹性蛋白降解、大动脉僵硬和增厚的主要决定因素 代谢综合征患者的收缩压；2)20-羟色胺依赖的MMP12 激活是老年人大动脉僵硬和收缩压的主要决定因素 代谢综合征；3)动脉壁或内脏脂肪组织是主要来源 20-HETE和MMP12导致大动脉僵硬和收缩血增加 代谢综合征中的压力。这些研究的结果可能对管理层来说很重要 单纯的收缩期高血压。