Role of Nrf2 in Vascular Antioxidant Defense

Nrf2 在血管抗氧化防御中的作用

• 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
• 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

 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（由申请人提供）：血管氧化应激是多种心血管疾病的共同特征，但基于施用抗氧化剂的治疗方法令人惊讶地令人失望。因此，人们对直接 上调内源性抗氧化防御作为与氧化应激相关的病理状况中的潜在治疗策略。这些策略的一个有吸引力的靶标是主抗氧化剂和细胞保护性转录因子核因子（红细胞衍生物2）样-2（NRF 2），其调节多种抗氧化剂和细胞保护性基因的表达，所述多种抗氧化剂和细胞保护性基因潜在地涉及超过200种不同的人类疾病。这个项目将使用一个新的和强大的实验模型（Nrf 2（-/-）敲除大鼠）以检验总体假设，即Nrf 2调节的酶的下调在高盐（HS）饮食发生的血管氧化应激中起主要作用;以及防止盐-诱导的ANG II抑制或施用已知上调NRF 2系统的化合物将改善内皮功能障碍和受损的血管内皮细胞。血管生成与饮食盐摄入量增加有关。具体目的#1是检验以下假设：恢复正常血浆ANG II水平和给予mas受体激动剂通过共同途径（ERK 1/2激活）改善HS喂养动物的血管氧化应激和内皮功能障碍，导致NRF 2抗氧化防御系统激活。具体目标#2是检验以下假设：恢复正常血浆ANG II水平和给予mas受体激动剂通过共同途径（ERK 1/2激活）预防盐诱导的微血管稀疏，导致NRF 2介导的抗氧化防御机制上调;以及NRF 2系统的直接上调将改善盐诱导的ANG II抑制存在下的血管生成反应。鉴于了解心血管疾病中性别相关差异的重要性以及有关女性NRF 2抗氧化防御的信息相对稀缺，我们将研究扩展到包括雄性和雌性大鼠。由于NRF 2在调节抗氧化防御中的普遍重要性，这些研究将为盐诱导的氧化应激和血管功能障碍的机制提供有价值的见解;并可能导致基于直接上调NRF 2调节的抗氧化防御机制的心血管疾病的有效治疗方法的发展。