Targeting ACE2 ubiquitination for hypertension

靶向 ACE2 泛素化治疗高血压

基本信息

  • 批准号:
    10318183
  • 负责人:
  • 金额:
    $ 60.05万
  • 依托单位:
  • 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 2023-11-30
  • 项目状态:
    已结题

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 导致心血管疾病(CVD)和全球死亡率的因素,因此仍然是一个越来越重要的因素。 重要医疗和公共卫生问题。肾素-血管紧张素系统(RAS)在维持高血压中的作用 正常血压(BP)和导致高血压的神经-心血管失调, 牢固确立。血管紧张素(Ang)-II,通过其1型受体(AT 1 R),促进交感神经的增加, 活性、盐和水重吸收、血管收缩、醛固酮和加压素释放和炎症, 所有这些都会导致高血压。血管紧张素转换酶2(ACE 2),最新发现的一种 该系统的成员切割Ang-II并产生Ang-(1-7),Ang-(1-7)起补偿作用, RAS的有害影响。除了确立ACE 2在预防神经源性疾病中的关键作用外, 在高血压中,我们的小组首次报道Ang-II通过介导ACE 2泛素化和降解, AT 1 R活化,通过溶酶体抑制剂预处理预防的效应。虽然证实, 尽管这些研究是独立的,但预防ACE 2泛素化和降解的治疗潜力尚未得到证实。 研究了我们的试验数据表明,ACE 2的C-末端突变阻止了泛素化, 保留了ACE 2的代偿活性,而用泛素化抗性ACE 2病毒治疗则钝化了ACE 2的代偿活性。 Ang-II介导的高血压在缺乏ACE 2的小鼠中的发展。此外,我们表明, 靶向E3泛素连接酶的主要家族NEDD 4,中和Ang-II对ACE 2的有害作用 活性,而试点蛋白质组学分析强调了其他E3连接酶的性别特异性调节, 盐敏感性高血压小鼠下丘脑中的泛素酶。我们的初步数据进一步 强调该机制不限于AT 1 R,而是由炎性细胞激活缓激肽B1 R, 与高血压相关的反应,也参与其中。因此,这项工作的假设是,RAS过度- 活化和高血压相关炎症加剧ACE 2泛素化,导致增强的 这种酶的降解及其代偿活性的丧失,最终加重高血压。这里我们 将使用新的病毒方法和独特的转基因模型靶向ACE 2泛素化,重点是 中枢神经系统和脉管系统中的性别和细胞特异性差异。验证我们的 这一假设将为新的靶向方法打开大门,目的是保持ACE 2的代偿活性, 高血压和心血管疾病。

项目成果

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ERIC D LAZARTIGUES其他文献

ERIC D LAZARTIGUES的其他文献

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{{ truncateString('ERIC D LAZARTIGUES', 18)}}的其他基金

Targeting ADAM17 maturation in resistant hypertension.
靶向顽固性高血压中 ADAM17 的成熟。
  • 批准号:
    10608153
  • 财政年份:
    2022
  • 资助金额:
    $ 60.05万
  • 项目类别:
Targeting ADAM17 maturation in resistant hypertension.
靶向顽固性高血压中 ADAM17 的成熟。
  • 批准号:
    10432585
  • 财政年份:
    2022
  • 资助金额:
    $ 60.05万
  • 项目类别:
SARS-CoV-2 tropism in the brain and its relationship to COVID-19 pathogenesis
SARS-CoV-2 在大脑中的趋向性及其与 COVID-19 发病机制的关系
  • 批准号:
    10272724
  • 财政年份:
    2021
  • 资助金额:
    $ 60.05万
  • 项目类别:
COVID19: SARS-CoV-2 and ACE2 interaction in hypertension
COVID19:SARS-CoV-2 和 ACE2 在高血压中的相互作用
  • 批准号:
    10152313
  • 财政年份:
    2021
  • 资助金额:
    $ 60.05万
  • 项目类别:
COVID19: SARS-CoV-2 and ACE2 interaction in hypertension
COVID19:SARS-CoV-2 和 ACE2 在高血压中的相互作用
  • 批准号:
    10398819
  • 财政年份:
    2021
  • 资助金额:
    $ 60.05万
  • 项目类别:
Targeting ACE2 ubiquitination for hypertension
靶向 ACE2 泛素化治疗高血压
  • 批准号:
    10534148
  • 财政年份:
    2019
  • 资助金额:
    $ 60.05万
  • 项目类别:
New strategies to restore ACE2 compensatory activity in neurogenic hypertension
恢复神经源性高血压中 ACE2 代偿活性的新策略
  • 批准号:
    10266017
  • 财政年份:
    2018
  • 资助金额:
    $ 60.05万
  • 项目类别:
Effects of ACE2 gene therapy on Diabetes
ACE2基因治疗对糖尿病的影响
  • 批准号:
    7895432
  • 财政年份:
    2010
  • 资助金额:
    $ 60.05万
  • 项目类别:
Effects of ACE2 gene therapy on Diabetes
ACE2基因治疗对糖尿病的影响
  • 批准号:
    8102099
  • 财政年份:
    2010
  • 资助金额:
    $ 60.05万
  • 项目类别:
P7: BRAIN-TARGETED ACE2 OVEREXPRESSION AND BLOOD PRESSURE REGULATION
P7:针对大脑的 ACE2 过度表达和血压调节
  • 批准号:
    7959748
  • 财政年份:
    2009
  • 资助金额:
    $ 60.05万
  • 项目类别:

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