Cytochrome P450 overexpression and hypertension in SHR

SHR 中细胞色素 P450 过度表达与高血压

• 批准号: 6953913
• 负责人: SCOTT H CARLSON
• 金额: $ 18.67万
• 依托单位: LUTHER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953913
• 关键词: blood pressure; cardiovascular disorder risk; cytochrome P450; denervation; disease /disorder etiology; disease /disorder model; eicosanoids; gene expression; genetic models; glomerular filtration rate; hemodynamics; hypertension; hypotension; kidney circulation; laboratory rat; portal hypertension; pulmonary artery; respiratory circulation disorder; spontaneous hypertensive rat; sympathetic nervous system; telemetry; vascular resistance; vasomotion

DESCRIPTION (provided by applicant): Hypertension is one of the leading causes of cardiovascular disease and stroke, accounting for nearly one-half of all deaths in the United States. Additionally, the presence of hypertension magnifies the adverse effects of renal failure and diabetes. However, the exact etiology of hypertension is unknown. To investigate mechanisms associated with the development of high blood pressure, research has increasingly incorporated rodent models of hypertension such as the Spontaneously Hypertensive Rat (SHR). Cytochrome P450 4A (CYP) is overexpressed in SHR, resulting in elevated levels of 20-HETE, a potent vasoconstrictor and natriuretic factor. However, the role of 20-HETE in the development and maintenance of hypertension in SHR is unclear. Further, it is not known whether the nervous system influences CYP expression levels in SHR. The proposed studies will explore whether CYP overexpression contributes to hypertension in both SHR and an experimental model in which hypertension is concomitantly expressed with portal hypertension and pulmonary dysfunction. The studies will examine the independent contribution of CYP overexpression on regional vascular hemodynamics and renal function in conscious animals, and will further explore a potential relationship between CYP expression levels and the nervous system. Specifically, the proposed studies will test the hypotheses that: Specific Aim 1. CYP overexpression alters both renal hemodynamics, including vascular tone, blood flow and GFR, and non-renal peripheral resistance in SHR. Specific Aim 2. The development of hypertension in SHR is driven by alterations in CYP expression secondary to increased sympathetic nervous system activity. Specific Aim 3. CYP overexpression contributes to portal hypertension and pulmonary dysfunction in hepatic denervated rats.

描述（由申请人提供）：高血压是心血管疾病和中风的主要原因之一，占美国所有死亡人数的近一半。此外，高血压的存在放大了肾衰竭和糖尿病的不良影响。然而，高血压的确切病因尚不清楚。为了研究与高血压发展相关的机制，研究越来越多地纳入高血压的啮齿动物模型，如自发性高血压大鼠（SHR）。细胞色素P450 4A（CYP 450）在SHR中过表达，导致20-HETE（一种有效的血管收缩剂和利钠因子）水平升高。然而，20-HETE在SHR高血压的发展和维持中的作用尚不清楚。此外，尚不清楚神经系统是否会影响SHR中的β-淀粉样蛋白表达水平。拟开展的研究将探讨在SHR和实验模型（高血压伴发门脉高压和肺功能障碍）中，β-淀粉样蛋白过度表达是否会导致高血压。这些研究将检查在清醒的动物中过表达的局部血管血流动力学和肾功能的独立贡献，并将进一步探讨过表达水平和神经系统之间的潜在关系。具体而言，拟议的研究将测试假设：具体目标1。SHR中，VEGF过度表达改变了肾脏血流动力学，包括血管张力、血流量和GFR，以及非肾脏外周阻力。具体目标2。SHR高血压的发展是由继发于交感神经系统活动增加的β-淀粉样蛋白表达的改变驱动的。具体目标3。去肝神经大鼠门脉高压和肺功能不全的病理机制研究