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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.