DDAH1 effects on the development of congestive heart failure

DDAH1 对充血性心力衰竭发展的影响

基本信息

  • 批准号:
    7869741
  • 负责人:
  • 金额:
    $ 30.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-05-01 至 2012-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): DDAH1 effects on the development of congestive heart failure Abstract Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) is important in maintaining vascular endothelial function and in protecting the heart from adverse ventricular remodeling. Accumulation of the endogenous NOS inhibitors asymmetric dimethyl arginine (ADMA) and Ng-monomethyl-L-arginine (L-NMMA) is a major independent risk factor for cardiovascular diseases including hypertension, congestive heart failure and atherosclerosis. These endogenous NOS inhibitors compete with L-arginine to inhibit NO production by eNOS. ADMA and L-NMMA are eliminated principally by metabolism to L-citrulline by dimethylarginine dimethylaminohydrolase (DDAH). DDAH1 and DDAH2 are encoded by two different genes. We have generated preliminary data indicating that DDAH1 rather than DDAH2 plays the essential role in degrading the NOS inhibitors in tissues such as kidney and brain and thereby regulating NO bioavailability in these tissues. In the heart we find DDAH1 expressed both in coronary endothelium and under the sarcolemma of cardiac myocytes. To address the cell specific role of DDAH1 in regulating endogenous NOS inhibitors, NO bioavailability and cardiovascular function, we have generated three novel tissue specific DDAH1 KO mouse strains. Using these new strains, we propose studies to determine whether the cardioprotective effect of DDAH1 resides in DDAH1 expressed in the cardiac myocytes or in the coronary endothelium. Specific aims will be addressed: (i) Determine the role of total-DDAH1, and DDAH1 expressed in the vascular endothelium in degrading myocardial ADMA and L-NMMA using endothelial specific and global DDAH1 gene deficient mice; (ii) Determine the cardiac protective effect from DDAH1 expressed in the cardiomyocytes on the development of heart failure produced by chronic systolic overload; and (iii) elucidate the protective effect from DDAH1 expressed in the vascular endothelium on the development of heart failure after chronic systolic overload. We will examine both changes in NO production and ROS generation in the different KO mouse strains. These unique tissue specific DDAH1 KO mice generated in our laboratory will allow us to elucidate cell type specific actions of DDAH1, as well as molecular mechanisms by which DDAH1 protects the overloaded heart. PUBLIC HEALTH RELEVANCE: Cardiovascular disease ranks as America's No. 1 killer that accounts for nearly one million deaths each year. Nitric oxide (NO) is known to exert protective effects on the heart. Accumulation of the endogenous nitric oxide synthase (NOS) inhibitors ADMA and L-NMMA is associated with increased cardiac death and the development of various cardiovascular diseases such as hypertension, coronary disease, atherosclerosis and congestive heart failure (CHF). ADMA and L-NMMA are degraded by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). However, our understanding of the physiology and pathology of this NOS inhibitor system is very limited. For example, although DDAH is reported to increase NO bioavailability by degradation of ADMA and L-NMMA, the in vivo role of DDAH1 vs. DDAH2 in regulating NO bioavailability is not clear. In addition, it is not known whether chronic accumulation of these endogenous NOS inhibitors can directly cause or exacerbate cardiovascular disease. The studies proposed in this application will use unique tissue specific KO mice generated in our laboratory to elucidate both isoform- and cell type specific actions of DDAH. The central hypotheses to be tested are that (i) DDAH1 (not DDAH2) is the essential or sole enzyme responsible for degradation of ADMA and LNMMA in cardiovascular system, (ii) deletion of endothelial DDAH1 will cause accumulation of the endogenous NOS inhibitors and systemic hypertension, and (iii) deletion of DDAH1 will exacerbate the development of CHF in the overloaded heart by decreasing NO bioavailability. We have concrete preliminary data to support these hypotheses. We will examine the influence of chronic accumulation of ADMA and L-NMMA on myocardial NO-bioavailability and on NOS-derived ROS generation. Finally, we will determine whether deletion of DDAH1 in endothelium or in cardiac myocytes impairs the ability of the heart to adapt to chronic pressure overload produced by transverse aortic constriction in mice. These studies will provide new knowledge regarding how DDAH1 acts to regulate production of NO and NOS-derived ROS, and demonstrate whether dysregulation of DDAH1 in either cardiac myocytes or endothelium can contribute to the development of CHF.
描述(由申请人提供): 内皮型一氧化氮合酶(endothelialnitricoxidesynthase,eNOS)产生的一氧化氮(nitricoxide,NO)在维持血管内皮功能和保护心脏免受心室重构中起重要作用。内源性NOS抑制剂不对称二甲基精氨酸(ADMA)和N-单甲基-L-精氨酸(L-NMMA)的蓄积是心血管疾病(包括高血压、充血性心力衰竭和动脉粥样硬化)的主要独立危险因素。这些内源性NOS抑制剂与L-精氨酸竞争抑制eNOS产生NO。ADMA和L-NMMA主要通过二甲基精氨酸二甲氨基水解酶(DDAH)代谢为L-瓜氨酸而消除。DDAH 1和DDAH 2由两个不同的基因编码。我们已经产生了初步的数据表明,DDAH 1,而不是DDAH 2在降解NOS抑制剂在组织,如肾脏和大脑,从而调节NO在这些组织中的生物利用度发挥着至关重要的作用。在心脏中,我们发现DDAH 1在冠状动脉内皮和心肌细胞的肌膜下表达。为了解决DDAH 1在调节内源性NOS抑制剂、NO生物利用度和心血管功能中的细胞特异性作用,我们产生了三种新的组织特异性DDAH 1 KO小鼠品系。使用这些新的菌株,我们提出的研究,以确定是否DDAH 1的心脏保护作用驻留在心肌细胞或冠状动脉内皮细胞中表达的DDAH 1。具体目标将被解决:(i)确定总DDAH 1和DDAH 1在血管内皮中表达的作用,使用内皮特异性和整体DDAH 1基因缺陷小鼠降解心肌ADMA和L-NMMA;(ii)确定心肌细胞中表达的DDAH 1对慢性收缩超负荷引起的心力衰竭的发展的心脏保护作用;以及(iii)阐明血管内皮中表达的DDAH 1对慢性收缩超负荷后心力衰竭发展的保护作用。我们将研究不同KO小鼠品系中NO产生和ROS产生的变化。这些独特的组织特异性DDAH 1基因敲除小鼠在我们的实验室中产生将使我们能够阐明DDAH 1的细胞类型特异性作用,以及DDAH 1保护过载心脏的分子机制。 公共卫生关系: 心血管疾病是美国的头号杀手,每年造成近100万人死亡。一氧化氮(NO)是已知的发挥对心脏的保护作用。内源性一氧化氮合酶(NOS)抑制剂ADMA和L-NMMA的积累与心源性死亡增加和各种心血管疾病如高血压、冠状动脉疾病、动脉粥样硬化和充血性心力衰竭(CHF)的发展相关。ADMA和L-NMMA被二甲基精氨酸二甲基氨基水解酶(DDAH)降解。然而,我们对NOS抑制剂系统的生理学和病理学的理解非常有限。例如,尽管报道DDAH通过降解ADMA和L-NMMA增加NO生物利用度,但DDAH 1与DDAH 2在调节NO生物利用度中的体内作用尚不清楚。此外,目前尚不清楚这些内源性NOS抑制剂的长期积累是否会直接导致或加剧心血管疾病。本申请中提出的研究将使用我们实验室中产生的独特组织特异性KO小鼠来阐明DDAH的亚型和细胞类型特异性作用。待检验的中心假设是:(i)DDAH 1(而不是DDAH 2)是心血管系统中负责降解ADMA和LNMMA的必需酶或唯一酶,(ii)内皮DDAH 1缺失将导致内源性NOS抑制剂蓄积和全身性高血压,以及(iii)DDAH 1缺失将通过降低NO生物利用度加剧超负荷心脏中CHF的发展。我们有具体的初步数据来支持这些假设。我们将研究ADMA和L-NMMA的慢性积累对心肌NO生物利用度和NOS衍生的ROS产生的影响。最后,我们将确定是否在内皮细胞或心肌细胞中缺失DDAH 1损害心脏适应小鼠横向主动脉缩窄所产生的慢性压力超负荷的能力。这些研究将提供有关DDAH 1如何调节NO和NOS衍生的ROS产生的新知识,并证明心肌细胞或内皮细胞中DDAH 1的失调是否有助于CHF的发展。

项目成果

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YINGJIE CHEN其他文献

YINGJIE CHEN的其他文献

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{{ truncateString('YINGJIE CHEN', 18)}}的其他基金

Mechanism of  PD1 on cardiac inflammation resolution during heart failure development
PD1 在心力衰竭发展过程中解决心脏炎症的机制
  • 批准号:
    10557113
  • 财政年份:
    2022
  • 资助金额:
    $ 30.2万
  • 项目类别:
Mechanism of  PD1 on cardiac inflammation resolution during heart failure development
PD1 在心力衰竭发展过程中解决心脏炎症的机制
  • 批准号:
    10345497
  • 财政年份:
    2022
  • 资助金额:
    $ 30.2万
  • 项目类别:
Mechanisms of Treg and IL-35 in Regulating LV Failure-induced Lung Remodeling and Right Heart Hypertrophy
Treg 和 IL-35 调节左室衰竭所致肺重塑和右心肥厚的机制
  • 批准号:
    10199004
  • 财政年份:
    2018
  • 资助金额:
    $ 30.2万
  • 项目类别:
Mechanisms of Treg and IL-35 in Regulating LV Failure-induced Lung Remodeling and Right Heart Hypertrophy
Treg 和 IL-35 调节左室衰竭所致肺重塑和右心肥厚的机制
  • 批准号:
    10116063
  • 财政年份:
    2018
  • 资助金额:
    $ 30.2万
  • 项目类别:
Molecular mechanism of 4E-binding proteins on heart failure development
4E结合蛋白对心力衰竭发展的分子机制
  • 批准号:
    8461159
  • 财政年份:
    2011
  • 资助金额:
    $ 30.2万
  • 项目类别:
Regulation of the novel mTOR suppressor DDIT4 in the failing heart
新型 mTOR 抑制剂 DDIT4 在衰竭心脏中的调节
  • 批准号:
    8113127
  • 财政年份:
    2011
  • 资助金额:
    $ 30.2万
  • 项目类别:
Molecular mechanism of 4E-binding proteins on heart failure development
4E结合蛋白对心力衰竭发展的分子机制
  • 批准号:
    8666798
  • 财政年份:
    2011
  • 资助金额:
    $ 30.2万
  • 项目类别:
Regulation of the novel mTOR suppressor DDIT4 in the failing heart
新型 mTOR 抑制剂 DDIT4 在衰竭心脏中的调节
  • 批准号:
    8244427
  • 财政年份:
    2011
  • 资助金额:
    $ 30.2万
  • 项目类别:
Molecular mechanism of 4E-binding proteins on heart failure development
4E结合蛋白对心力衰竭发展的分子机制
  • 批准号:
    8183136
  • 财政年份:
    2011
  • 资助金额:
    $ 30.2万
  • 项目类别:
Molecular mechanism of 4E-binding proteins on heart failure development
4E结合蛋白对心力衰竭发展的分子机制
  • 批准号:
    8311646
  • 财政年份:
    2011
  • 资助金额:
    $ 30.2万
  • 项目类别:

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