权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting ACE2 ubiquitination for hypertension

靶向 ACE2 泛素化治疗高血压

基本信息

批准号：
10534148
负责人：
ERIC D LAZARTIGUES
金额：
$ 60.05万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-26 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10534148
关键词：
ACE2 Affect Age Aldosterone Angiotensin II Angiotensins Blood Pressure Bradykinin Brain Cardiovascular Diseases Cardiovascular system Cells Central Nervous System Data Development Dominant-Negative Mutation Endothelial Cells Enzymes Family Family member Female G-Protein-Coupled Receptors Gender Hypertension Hypothalamic structure Impairment In Vitro Individual Inflammation Inflammatory Inflammatory Response Kinins Knockout Mice Laboratories Ligase Lysine Lysosomes Maintenance Mediating Medical Modeling Molecular Mus Mutation Neurons Peptidyl-Dipeptidase A Play Population Prevalence Prevention Proteomics Public Health Pulmonary Hypertension Receptor Activation Renin-Angiotensin System Reporting Resistance Risk Factors Role Site Sodium Chloride System Telemetry Testing Therapeutic Transfection Transgenic Model Transgenic Organisms Ubiquitin Ubiquitination United States Validation Vasopressins Viral Virus Water Work absorption aged conditional knockout gene therapy hypertension treatment in vitro activity in vivo induced pluripotent stem cell inhibitor male member mortality mouse model mutant neurogenic hypertension novel novel strategies optogenetics pharmacologic preservation prevent receptor response salt sensitive hypertension tool ubiquitin isopeptidase ubiquitin-protein ligase vasoconstriction

项目摘要

With prevalence as high as 55% for individuals aged 55 and older in United States, hypertension is a major risk factor contributing to cardiovascular diseases (CVD) and global mortality, hence remaining an increasingly important medical and public health issue. The role of the renin-angiotensin system (RAS) in the maintenance of normal blood pressure (BP) and in the neuro-cardiovascular dysregulation leading to hypertension has been firmly established. Angiotensin (Ang)-II, by means of its type 1 receptor (AT1R), promotes increased sympathetic activity, salt and water reabsorption, vasoconstriction, aldosterone and vasopressin release and inflammation, all contributing to hypertension. Angiotensin Converting Enzyme type 2 (ACE2), one of the latest identified members of this system cleaves Ang-II and produces Ang-(1-7) which plays a compensatory role and opposes the RAS deleterious effects. Beyond establishing ACE2 as a critical player in the prevention of neurogenic hypertension, our group was the first to report that Ang-II mediates ACE2 ubiquitination and degradation via AT1R activation, effects that were prevented by pretreatment with a lysosomal inhibitor. Although confirmed by independent groups, the therapeutic potential of preventing ACE2 ubiquitination and degradation has not been investigated. Our pilot data, show that mutation of the C-terminus of ACE2 prevents the ubiquitination and preserves ACE2 compensatory activity while treatment with an ubiquitination-resistant ACE2 virus blunts the development of Ang-II-mediated hypertension in mice otherwise lacking ACE2. In addition, we show that targeting NEDD4, a major family of E3 ubiquitin ligases, neutralizes the deleterious effects of Ang-II on ACE2 activity, while a pilot proteomics analysis highlighted gender-specific modulation of other E3 ligases and de- ubiquitinases in the hypothalamus of mice undergoing salt-sensitive hypertension. Our preliminary data further highlight that this mechanism is not restricted to AT1R but that bradykinin B1R, activated by the inflammatory response associated to hypertension, are also involved. Thus, the hypothesis of this work is that RAS over- activation and hypertension-associated inflammation exacerbate ACE2 ubiquitination, resulting in enhanced degradation of this enzyme and a loss of its compensatory activity, ultimately reinforcing hypertension. Here, we will target ACE2 ubiquitination using novel viral approaches and unique transgenic models with an emphasis on gender- and cell-specific differences in the central nervous system and the vasculature. Validation of our hypothesis will open the door for new targeting approaches aimed at preserving ACE2 compensatory activity in hypertension and CVD.

在美国，55岁及以上人群的患病率高达55%，高血压是一种主要风险