Natriuretic Peptide System and Cardiac Fibrosis

利钠肽系统与心脏纤维化

• 批准号: 7898654
• 负责人: John C Burnett
• 金额: $ 34.57万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 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/7898654
• 关键词: Address; Agonist; Animal Model; Antihypertensive Agents; Attenuated; Biology; CTF1 gene; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell Cycle; Cell Cycle Progression; Cell Therapy; Chronic; Clinical; 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; 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; cGMP production; clinically relevant; conventional therapy; cyclin E-dependent kinase; design; hemodynamics; hypertensive heart disease; improved; improved functioning; in vivo; inhibitor/antagonist; innovation; insight; novel; oncoprotein p21; pressure; prevent; receptor; translational study

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 激活因子作为新颖有效的慢性治疗策略，以减轻高血压心脏病 (HHD) 中心脏纤维化的发展。在这里，我们提出研究针对颗粒鸟苷酸环化酶 (pGC) 的利钠肽 (NP) 和一种不依赖一氧化氮 (NO) 直接靶向可溶性鸟苷酸环化酶 (sGC) 的新型化合物 BAY 41-2272 (BAY)。我们还建议定义 HHD 中抗纤维化 cGMP 疗法的心脏保护益处，这些益处超越传统疗法，除了改善心肌结构之外还增强心肌功能。此外，我们还建议对 NP 和 BAY 抑制心脏成纤维细胞 (CF) 增殖的机制进行新的见解，特别关注这些 cGMP 激活化合物抑制细胞周期的分子机制 进展。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： 目标 1：与慢性噻嗪类利尿剂治疗相比，确定 HHD 中长期 BNP 或 CBNP 治疗的 pGC 激活的抗纤维化和心肌特性。假设：慢性 NP 治疗在预防 HHD 患者心脏纤维化、抑制促纤维化因子激活、改善心室功能和增强心肌灌注方面优于噻嗪类利尿剂治疗。目标 2：与慢性噻嗪类利尿剂治疗相比，确定 HHD 中长期 BAY 治疗慢性 sGC 激活的抗纤维化和心肌特性。假设：慢性 BAY 治疗在预防 HHD 患者心脏纤维化、抑制促纤维化因子激活、改善心室功能和增强心肌灌注方面优于噻嗪类利尿剂治疗。目标 3：在从正常和 HHD 心脏分离的 CF 中确定 NP 和 BAY 抑制 CT-1 和 ET-1 诱导的细胞周期进程的机制。假设：NPs 激活 pGC 或 sGC 激活 BAY 的产品将通过 cGMP 生产，降低细胞周期蛋白 D1 和 E、Rb 磷酸化状态，并增加 p16 和 p21 蛋白，从而抑制进入细胞周期的 S 期。