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Natriuretic Peptide System and Cardiac Fibrosis

利钠肽系统与心脏纤维化

基本信息

批准号：
7674287
负责人：
John C Burnett
金额：
$ 38.5万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7674287
关键词：
Address Agonist Animal Model Antihypertensive Agents Attenuated BAY 41-2272 CDKN1A gene CTF1 gene Cardiac Cardiovascular Diseases Cell Cycle Cell Cycle Progression Cell Therapy Chronic Class Clinical Copy Number Polymorphism Coronary Cyclic GMP Cyclin D1 Cyclin-Dependent Kinases Cyclins Dependency Development Endocrine Endothelin-1 Fibroblasts Fibrosis Functional disorder Generations Genes Goals Guanylate Cyclase Harvest Heart Knowledge Methodology Microvascular Permeability Modeling Molecular Myocardial Myocardial perfusion Natriuretic Peptides Nitrates Nitric Oxide Nitrosation Particulate Peptides Pharmaceutical Preparations Phase Phosphorylation Production Property Proteins Receptor Activation Retinoblastoma Protein Small Interfering RNA Soluble Guanylate Cyclase Structure Superoxides System Therapeutic Thiazide Diuretics Time Up-Regulation Ventricular Ventricular Dysfunction Ventricular Function Work base clinically relevant cyclin E-dependent kinase design hemodynamics hypertensive heart disease improved improved functioning in vivo inhibitor/antagonist innovation insight nitrate novel oncoprotein p21 pressure prevent receptor translational study

项目摘要

The broad objective of this revised project is to establish cGMP-activating factors as novel and effective chronic therapeutic strategies to attenuate the development of cardiac fibrosis in hypertensive heart disease (HHD). Here we propose studies of the Natriuretic Peptides (NPs) that target particulate guanylyl cyclase (pGC) and a novel new compound BAY 41-2272 (BAY) that directly targets soluble guanylyl cyclase (sGC) independent of Nitric Oxide (NO). We also propose to define cardioprotective benefits of anti-fibrotic cGMP therapies in HHD that go beyond conventional therapies to enhance myocardial function in addition to improving myocardial structure. Further, we also propose to define new insights into the mechanisms by which the NPs and BAY inhibit cardiac fibroblast (CF) proliferation with a specific focus on molecular mechanisms whereby these cGMP-activating compounds inhibit cellcycle progression. Thus, Project 2 addresses the Central Theme of all projects that is innovative therapeutic strategies for cardiovascular disease. Our Specific Aims and Hypotheses are as follows: Aim 1: Determine the anti-fibrotic and myocardial properties of pGC activation with chronic BNP or CBNP therapy in HHD compared to chronic thiazide diuretic therapy. Hypothesis: Chronic NP therapy will be superior to thiazide diuretic therapy in preventing cardiac fibrosis, suppressing activation of profibrotic factors, improving ventricular function and enhancing myocardial perfusion in HHD. Aim 2: Determine the anti-fibrotic and myocardial properties of chronic sGC activation with chronic BAY therapy in HHD compared to chronic thiazide diuretic therapy. Hypothesis: Chronic BAY therapy will be superior to thiazide diuretic therapy in preventing cardiac fibrosis, suppressing activation of pro-fibrotic factors, improving ventricular function and enhancing myocardial perfusion in HHD. Aim 3: Determine in CFs isolated from normal and HHD hearts the mechanism(s) by which the NPs and BAY inhibit cell cycle progression induced by CT-1 and ET-1. Hypothesis: pGC activation by the NPs or sGC activation by BAY will, via cGMP production, decrease cyclin D1 and E, Rb phosphorylation status, and increase p16 and p21 proteins and thus inhibit entrance into the S-phase of the cell cycle.

该修订项目的总体目标是建立cgmp激活因子作为一种新的有效的慢性治疗策略，以减轻高血压心脏病（HHD）心脏纤维化的发展。在此，我们提出了针对颗粒型鸟苷环化酶（pGC）的利钠肽（NPs）和一种不依赖于一氧化氮（NO）直接靶向可溶性鸟苷环化酶（sGC）的新化合物BAY 41-2272 （BAY）的研究。我们还建议确定抗纤维化cGMP治疗对HHD的心脏保护作用，除了改善心肌结构外，还可以增强心肌功能。此外，我们还建议对NPs和BAY抑制心脏成纤维细胞（CF）增殖的机制进行新的认识，并特别关注这些cgmp激活化合物抑制细胞周期的分子机制