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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.