Natriuretic Peptide System and Cardiomyocytes Biology

利尿钠肽系统和心肌细胞生物学

基本信息

批准号：
7898653
负责人：
Margaret M Redfield
金额：
$ 34.57万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7898653
关键词：
Address Adrenal Glands Age Atrial Natriuretic Factor Binding Biology Blood Blood Vessels Blood flow Brain natriuretic peptide C-Type Natriuretic Peptide Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cells Chronic Coronary Cyclic GMP Development Diastolic heart failure Dominant-Negative Mutation Dose Echocardiography Endothelial Cells Fibrosis Foundations Functional disorder Gene Transfer Techniques Guanylate Cyclase Heart Atrium Heart failure Hormonal Hormones Human Hypertension Hypertrophy Impairment Infusion procedures Intracellular Second Messenger Kidney Laboratories Left Left Ventricular Function Left ventricular structure Mediating Modeling Morbidity - disease rate Mus Mutation Myocardial Myocardium NPR2 gene Natriuretic Peptides Patients Peptides Production Property Proteins Relaxation Reporting Research Design Resources Second Messenger Systems Speed Structure Syndrome System Systolic heart failure Testing Therapeutic Transgenes Transgenic Model Transgenic Organisms Translations Treatment Efficacy Ventricular autocrine base blood pressure regulation gain of function gain of function mutation hypertensive heart disease improved mortality novel novel therapeutics overexpression paracrine peptide A polypeptide C population based pre-clinical pressure receptor response sex subcutaneous transgene expression

Address Adrenal Glands Age Atrial Natriuretic Factor Binding Biology Blood Blood Vessels Blood flow Brain natriuretic peptide C-Type Natriuretic Peptide Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cells Chronic Coronary Cyclic GMP Development Diastolic heart failure Dominant-Negative Mutation Dose Echocardiography Endothelial Cells Fibrosis Foundations Functional disorder Gene Transfer Techniques Guanylate Cyclase Heart Atrium Heart failure Hormonal Hormones Human Hypertension Hypertrophy Impairment Infusion procedures Intracellular Second Messenger Kidney Laboratories Left Left Ventricular Function Left ventricular structure Mediating Modeling Morbidity - disease rate Mus Mutation Myocardial Myocardium NPR2 gene Natriuretic Peptides Patients Peptides Production Property Proteins Relaxation Reporting Research Design Resources Second Messenger Systems Speed Structure Syndrome System Systolic heart failure Testing Therapeutic Transgenes Transgenic Model Transgenic Organisms Translations Treatment Efficacy Ventricular autocrine base blood pressure regulation gain of function gain of function mutation hypertensive heart disease improved mortality novel novel therapeutics overexpression paracrine peptide A polypeptide C population based pre-clinical pressure receptor response sex subcutaneous transgene expression

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项目摘要

Our broad objective is to establish that the natriuretic peptide system (NPS), via direct autocrine effects on the cardiomyocyte and paracrine effects on non-myocyte cardiac cells, is a key regulator of diastolic left ventricular (LV) function. Further, we propose to establish that enhancement of cardiomyocyte NPS activity represents a cardiac specific and effective therapeutic strategy to ameliorate the diastolic dysfunction associated with hypertensive heart disease. The heart failure (HF) syndrome is primarily related to diastolic dysfunction (diastolic HF, DHF) in 40-50% of cases. Therapies that specifically improve diastolic function in DHF are lacking. The natriuretic peptides (atrial and brain natriuretic peptide, ANP and BNP) stimulate production of the intracellular second messenger cGMP via binding to the natriuretic peptide A (NPRA) receptor. While traditionally viewed as circulating hormones that modulate volume and homeostasis and blood pressure via systemic effects, the presence of NPRA receptors on cardiomyocytes and on non-myocyte cardiac cells suggests the potential for autocrine/paracrine effects of the NPS on myocardial structure and function. We have performed preliminary studies utilizing cardiac specific transgenic models with positive and negative functional mutations in the NPRA. Based on our findings, we hypothesize that 1) the NPS enhances LV relaxation via a direct effect on cardiomyocyte function mediated by stimulation of cardiomyocyte NPRA receptors; 2) the NPS reduces LV diastolic stiffness via direct effects on cardiac cardiomyocyte NPRA receptors which limit hypertrophy and effects on non-myocyte cardiac cells which limit fibrosis; 3) therapeutic strategies based on cardiac specific augmentation of NPS actions improve diastolic function in established hypertensive heart disease in a dose dependent fashion; and 4) therapeutic strategies based on systemic augmentation of NPS levels improve myocardial and chamber diastolic properties via direct myocardial and indirect systemic effects. The proposed studies use cardiac specific transgenesis in mice to study the effect of the NPS directly on cardiomyocytes. Specifically, we will generate models that express gain of function (GOF-NPRA) or dominant negative (DN-NPRA) mutations in NPRA or over-express wild-type NPRA (NPRA) in cardiomyocytes. We will use both conventional and conditionally expressed cardiac specific transgenic models. The use of conditionally expressed transgenes will allow us to begin transgene expression after the establishment of hypertensive heart disease. Over-expression of wild-type NPRA will allow us to explore the dose response of cardiac specific augmentation of NPS actions. Studies are designed to address three specific aims: 1) Determine if the NPS alters LV diastolic function (relaxation and stiffness) and LV structure via effects mediated by cardiomyocytes NPRA; 2) Determine if conditional over-expression of wild-type NPRA ameliorates diastolic dysfunction in established hypertensive heart disease; 3) determine if chronic systemic administration of brain natriuretic peptide (BNP) ameliorates diastolic dysfunction in established hypertensive heart disease and if these effects are more robust in the presence of functional cardiac NPRA receptors.

我们的广泛目标是确定纳地酸肽系统（NPS）是通过对心肌细胞和旁分泌对非肌细胞心脏细胞作用的直接影响，是舒张期左心室（LV）功能的关键调节剂。此外，我们建议确定心肌细胞NPS活性的增强代表了一种心脏特异性和有效的治疗策略，可以改善与高血压心脏病相关的舒张功能障碍。心力衰竭（HF）综合征主要与40-50％的病例中的舒张功能障碍（舒张期HF，DHF）有关。缺乏专门提高DHF舒张功能的疗法。亚钠肽（心房和脑力钠肽，ANP和BNP）通过结合与亚位曲尿肽A（NPRA）受体的结合来刺激细胞内第二信使CGMP的产生。尽管传统上被视为通过全身作用调节体积和稳态和血压的循环激素，但NPRA受体在心肌细胞和非肌细胞心脏细胞上的存在表明NPS对心肌结构和功能的自身分泌作用可能有可能。我们已经利用NPRA中具有正功能突变的心脏特异性转基因模型进行了初步研究。根据我们的发现，我们假设1）NPS增强了LV松弛通过对心肌细胞NPRA刺激介导的心肌细胞功能的直接影响受体； 2）NP通过对心脏心肌细胞NPRA受体的直接影响来降低LV舒张性刚度，从而限制了肥大并对限制纤维化的非肌细胞心脏细胞的影响； 3）基于心脏特异性增强NPS作用的治疗策略以剂量依赖性的方式改善了既定的高血压心脏病的舒张功能； 4）基于NPS水平的系统性增强的治疗策略通过直接心肌和间接的全身效应改善了心肌和腔室舒张特性。拟议的研究使用小鼠中使用心脏特异性转基因来直接研究NP对心肌细胞的影响。具体而言，我们将生成在NPRA或过表达野生型NPRA（NPRA）中表达功能增长（GOF-NPRA）或主导性野生型NPRA（NPRA）的模型。我们将使用常规和有条件表达的心脏特异性转基因模型。有条件表达的转基因的使用将使我们能够在建立高血压心脏病后开始转基因表达。野生型NPRA的过表达将使我们能够探索NPS动作的心脏特异性增强的剂量反应。研究旨在解决三个具体目标：1）确定NPS是否改变了LV舒张功能（松弛和刚度）和LV 通过心肌细胞NPRA介导的效应的结构； 2）确定野生型NPRA的有条件过表达是否可以改善既定高血压心脏病中的舒张功能障碍； 3）确定慢性全身施用脑坚脂肽（BNP）是否可以改善既定的高血压心脏病中的舒张功能障碍，并且在存在功能性心脏NPRA受体的情况下，这些作用是否更强大。