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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：
7674293
负责人：
John C Burnett
金额：
$ 40.29万
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/7674293
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.

这个修订项目的广泛目标是建立cGMP激活因子作为新的和有效的慢性治疗策略，以减轻高血压性心脏病(HHD)心脏纤维化的发展。在这里，我们提出了针对颗粒鸟酰环酶(PGC)的利钠肽(NPs)的研究，以及一种新的化合物BAY 41-2272(BAY)，它直接针对不依赖于一氧化氮(NO)的可溶性鸟苷酸环酶(SGC)。我们还建议确定抗纤维化cGMP治疗在HHD中的心脏保护益处，这些治疗超越了传统治疗，除了改善心肌结构外，还增强了心肌功能。此外，我们还建议对NPs和Bay抑制心脏成纤维细胞(CF)增殖的机制定义新的见解，特别关注这些cGMP激活化合物抑制细胞周期的分子机制。进步。因此，项目2解决了所有创新项目的中心主题心血管疾病的治疗策略。我们的具体目标和假设如下：目的1：确定慢性BNP或CBNP治疗HHD时PGC激活的抗纤维化和心肌特性，并与慢性噻嗪利尿剂治疗进行比较。假设：慢性NP治疗HHD在预防心肌纤维化、抑制促纤维化因子的激活、改善心功能、增强心肌血流灌注等方面优于噻嗪利尿剂治疗。目的：比较慢性BAY疗法和慢性噻嗪利尿剂疗法对慢性高血压患者sGC激活的抗纤维化和心肌特性的影响。假设：慢性海湾疗法在预防心肌纤维化、抑制促纤维化因子的激活、改善心功能和增强心肌血流灌注等方面优于噻嗪利尿剂疗法。目的：在分离的正常和高血压心脏CFs中，研究NPs和Bay抑制CT-1和ET-1诱导的细胞周期进程的机制(S)。假设：PGC由NPs或sGC激活 BAY通过cGMP的产生，降低细胞周期蛋白D1和E、Rb的磷酸化状态，增加p16和p21蛋白的表达，从而抑制进入细胞周期的S期。