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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：
8067882
负责人：
YINGJIE CHEN
金额：
$ 11.33万
依托单位：
UNIVERSITY OF MINNESOTA
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

来源：
https://reporter.nih.gov/project-details/8067882
关键词：
Accounting Address Americas Area Arginine Atherosclerosis Biological Assay Biological Availability Blood Vessels Brain Cardiac Cardiac Death Cardiac Myocytes Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cells Cessation of life Chronic Citrulline Clinical Congestive Heart Failure Coronary Coronary heart disease Cyclic GMP Data Development Endothelium Enzymes Functional disorder Generations Genes Goals Heart Heart failure Hypertension Isotope Labeling Kidney Knock-out Knowledge Laboratories Metabolism Molecular Mouse Strains Mus Myocardial Nitric Oxide Nitric Oxide Synthase Pathology Physiology Play Production Protein Isoforms Reactive Oxygen Species Regulation Reporting Research Personnel Risk Factors Role Sarcolemma Signal Transduction Site System Techniques Testing Therapeutic Tissues Transgenic Mice Vascular Endothelial Cell Vascular Endothelium Ventricular Remodeling abstracting cardiogenesis cell type constriction dimethylargininase experience human NOS3 protein improved in vivo inhibitor/antagonist innovation mouse model novel omega-N-Methylarginine pressure protective effect public health relevance therapeutic target

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）：

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cardiomyocyte dimethylarginine dimethylaminohydrolase-1 (DDAH1) plays an important role in attenuating ventricular hypertrophy and dysfunction.

心肌细胞二甲基精氨酸二甲氨基水解酶-1 (DDAH1) 在减轻心室肥厚和功能障碍中发挥重要作用

DOI：
10.1007/s00395-017-0644-z
发表时间：
2017-08-17
期刊：
Basic research in cardiology
影响因子：
9.5
作者：
Xu X;Zhang P;Kwak D;Fassett J;Yue W;Atzler D;Hu X;Liu X;Wang H;Lu Z;Guo H;Schwedhelm E;Böger RH;Chen P;Chen Y
通讯作者：
Chen Y

Delayed treatment effects of xanthine oxidase inhibition on systolic overload-induced left ventricular hypertrophy and dysfunction.

黄嘌呤氧化酶抑制对收缩期超负荷引起的左心室肥厚和功能障碍的延迟治疗效果。