Role of Nrf2 in Vascular Antioxidant Defense

Nrf2 在血管抗氧化防御中的作用

基本信息

批准号：
9334300
负责人：
JULIAN H LOMBARD
金额：
$ 44.39万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-17 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9334300
关键词：
Affect Agonist Ally American Angiotensins Animals Antioxidants Area Arteries Binding Blood Vessels Blood flow Brain Cardiovascular Diseases Cardiovascular system Cell Nucleus Cells Defense Mechanisms Development Diet Disease Dose Down-Regulation Effectiveness Enzymes Erythroid Event Exhibits Experimental Models Female Forearm Functional disorder GTP-Binding Protein alpha Subunits, Gs Genes Genetic Genetic Transcription Goals Growth Human Hypertension Impairment Infusion procedures Knock-out Lead Light MAPK3 gene Mediating Mission Modeling Mutation Nuclear Organ Oxidants Pathologic Pathway interactions Pear Physiological Plasma Play Prevention Promoter Regions Rat Strains Rattus Research Resistance Risk Factors Role Signal Transduction Sodium Chloride Stress System Testing Therapeutic Treatment Efficacy Up-Regulation Vascular Diseases angiogenesis antioxidant enzyme base bindin combat dietary salt endothelial dysfunction experimental study high salt diet human disease human subject improved insight interest male novel oxidant stress pressure prevent prognostic protective effect public health relevance receptor response restoration salt intake sex stem transcription factor volunteer

项目摘要

DESCRIPTION (provided by applicant): Vascular oxidant stress is a common feature of multiple cardiovascular diseases, but therapeutic approaches based on administration of antioxidants have been surprisingly disappointing. As a result, there is growing interest in direct upregulation of endogenous antioxidant defenses as a potential therapeutic strategy in pathological conditions associated with oxidant stress. One attractive target for these strategies is the master antioxidant and cell protective transcription factor nuclear factor (erythroid- derivd 2)-like-2 (NRF2), which regulates the expression of multiple antioxidant and cell protective genes that are potentially involved in over 200 different human diseases. This project will use a new and powerful experimental model (the Nrf2(-/-) knockout rat) to test the overall hypothesis that down-regulation of NRF2-regulated enzymes plays a major role in vascular oxidant stress occurring with high salt (HS) diet; and that prevention of salt-induced ANG II suppression or administration of compounds known to upregulate the NRF2 system will ameliorate the endothelial dysfunction and impaired angiogenesis associated with elevated dietary salt intake. Specific Aim #1 is to test the hypothesis that restoring normal plasma ANG II levels and administration of mas receptor agonists ameliorate vascular oxidant stress and endothelial dysfunction in HS-fed animals via a common pathway (ERK 1/2 activation), leading to activation of the NRF2 antioxidant defense system. Specific Aim #2 is to test the hypothesis that restoration of normal plasma ANG II levels and administration of mas receptor agonists prevent salt-induced microvascular rarefaction via a common pathway (ERK 1/2 activation), leading to upregulation of NRF2-mediated antioxidant defense mechanisms; and that direct upregulation of the NRF2 system will improve angiogenic responses in the presence of salt-induced ANG II suppression. We have expanded the study to include male and female rats in light of the importance of understanding sex-related differences in cardiovascular disease and the relative scarcity of information regarding NRF2 antioxidant defenses in females. Because of the pervasive importance of NRF2 in regulating antioxidant defenses, these studies will provide valuable insight into the mechanisms of salt-induced oxidant stress and vascular dysfunction; and could lead to the development of effective therapeutic approaches to cardiovascular diseases based on direct upregulation of NRF2-regulated antioxidant defense mechanisms.

描述（由适用提供）：氧化血管胁迫是多种心血管疾病的常见特征，但是基于抗氧化剂给药的治疗方法令人失望。结果，直接越来越感兴趣内源性抗氧化剂防御的上调是与氧化物应激相关的病理状况中潜在的治疗策略。这些策略的一个有吸引力的目标是主抗氧化剂和细胞保护的转录因子核因子（红细胞衍生物2）-2-2（NRF2），它调节了多种抗氧化剂和细胞保护基因的表达，这些基因可能与超过200多种不同的人类疾病有关。该项目将使用一种新的强大的实验模型（NRF2（ - / - ）敲除大鼠）来检验总体假设，即NRF2调节的酶的下调在高盐（HS）饮食的高盐（HS）饮食中发生的血管氧化物胁迫中起主要作用；并且预防盐诱导的ANG II抑制或施用已知的上调NRF2系统的化合物将改善内皮功能障碍和与饮食中盐摄入率升高有关的血管生成受损。具体目的1是测试以下假设：恢复正常的血浆ANG II水平并通过公共途径（ERK 1/2激活）改善HS-FED动物中的血管氧化剂应激和内皮功能障碍，从而导致NRF2抗氧化剂防御系统的激活。具体目的2是测试以下假设：恢复正常的血浆ANG II水平和MAS受体激动剂的给药，以防止通过公共途径（ERK 1/2激活）盐诱导的微血管稀疏性（ERK 1/2激活），从而导致NRF2介导的介导的抗氧化剂防御机制上调； NRF2系统的直接上调将在存在盐诱导的ANG II抑制的情况下改善血管生成反应。鉴于了解与性血管疾病中与性别相关的差异的重要性以及与女性NRF2抗氧化剂防御有关的信息相对稀缺，我们将研究扩展到包括男性和雌性大鼠。由于NRF2在确定抗氧化剂防御方面的普遍重要性，这些研究将为盐诱导的氧化物胁迫和血管功能障碍的机制提供宝贵的见解。并可能导致基于NRF2调节的抗氧化剂防御机制的直接上调来开发有效的心血管疾病治疗方法。