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

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.

我们的总体目标是通过对心肌细胞的直接自分泌作用和对非心肌细胞的心肌细胞的旁分泌作用，确定利钠肽系统（NPS）是舒张左心室（LV）功能的关键调节剂。此外，我们建议确定心肌细胞 NPS 活性的增强代表了改善与高血压心脏病相关的舒张功能障碍的心脏特异性且有效的治疗策略。 40-50% 的心力衰竭 (HF) 综合征主要与舒张功能障碍（舒张性 HF、DHF）相关。目前缺乏专门改善 DHF 舒张功能的疗法。利钠肽（心房和脑利钠肽、ANP 和 BNP）通过与利钠肽 A (NPRA) 受体结合，刺激细胞内第二信使 cGMP 的产生。虽然传统上被视为通过全身效应调节容量、体内平衡和血压的循环激素，但心肌细胞和非心肌细胞心肌细胞上 NPRA 受体的存在表明 NPS 对心肌结构和功能具有自分泌/旁分泌作用的潜力。我们利用 NPRA 中具有阳性和阴性功能突变的心脏特异性转基因模型进行了初步研究。根据我们的研究结果，我们假设 1) NPS 增强左心室舒张通过刺激心肌细胞 NPRA 介导对心肌细胞功能产生直接影响受体； 2) NPS 通过直接影响心肌细胞 NPRA 受体（限制肥大）和影响非心肌细胞（限制纤维化）来降低左心室舒张硬度； 3) 基于NPS作用的心脏特异性增强的治疗策略以剂量依赖性方式改善已确定的高血压性心脏病的舒张功能； 4) 基于 NPS 水平全身增强的治疗策略通过直接心肌和间接全身效应改善心肌和心室舒张特性。拟议的研究使用小鼠心脏特异性转基因来研究 NPS 直接对心肌细胞的影响。具体来说，我们将生成在 NPRA 中表达功能获得 (GOF-NPRA) 或显性失活 (DN-NPRA) 突变或在心肌细胞中过度表达野生型 NPRA (NPRA) 的模型。我们将使用传统的和条件表达的心脏特异性转基因模型。条件表达转基因的使用将使我们能够在高血压心脏病形成后开始转基因表达。野生型 NPRA 的过度表达将使我们能够探索心脏特异性增强 NPS 作用的剂量反应。研究旨在解决三个具体目标： 1) 确定 NPS 是否会改变 LV 舒张功能（松弛和僵硬）和 LV 通过心肌细胞 NPRA 介导的效应进行结构； 2) 确定野生型 NPRA 的条件性过度表达是否可以改善已确诊的高血压心脏病的舒张功能障碍； 3) 确定长期全身施用脑利钠肽 (BNP) 是否可以改善已确定的高血压心脏病的舒张功能障碍，以及这些作用在功能性心脏 NPRA 受体存在的情况下是否更加强劲。