Cardiovascular Peptides and Myocardial Infarction

心血管肽与心肌梗塞

• 批准号: 7269302
• 负责人: John C Burnett
• 金额: $ 49.17万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7269302
• 关键词: Acute myocardial infarction; Adrenergic Agents; Aldosterone; Animals; Anterior; Apoptotic; Area; Arts; Atrial Natriuretic Factor; Biological; Biological Markers; Biology; Blood Vessels; Blood capillaries; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Survival; Cells; Collagen; Complication; Coronary; Coronary Arteriosclerosis; Development; Dilatation - action; Disruption; Excretory function; Fibroblasts; Fibrosis; Functional disorder; Genes; Genetic Polymorphism; Goals; Heart; Heart Injuries; Heart failure; Hormones; Hour; Human; Hypertension; Impairment; Intravenous; Kidney; Laboratory Research; Lead; Magnetic Resonance Imaging; Mediating; Methodology; Modeling; Molecular; Mus; Mutation; Myocardial; Myocardial Infarction; Myocardium; Natriuresis; Natriuretic Peptides; Natural regeneration; Nuclear; Outcome; Oxygen Consumption; Pathological Dilatation; Peptides; Phase; Phenotype; Phosphotransferases; Physiological; Plasma; Prevention; Property; Proteins; Renal function; Renin-Angiotensin-Aldosterone System; Reporting; Research; Research Personnel; Risk; Sodium; Structure; System; Therapeutic; Therapeutic Agents; Thinking; Time; Translational Research; Vasodilation; Vasodilation disorder; Ventricular; Ventricular Dysfunction; Ventricular Remodeling; Wild Type Mouse; ZYX gene; adrenergic; base; capillary; cardiogenesis; clinically relevant; day; density; human study; innovation; mortality; mouse model; novel; prevent; programs; promoter; repaired; response; success

DESCRIPTION (provided by applicant): Our objective is to establish that the cardiac peptide BNP is a novel and efficacious therapy for human acute myocardial infarction (AMI) to preserve myocardial structure and function. This highly translational research takes advantage of the cardioprotective and renal enhancing properties of this small and endogenous peptide in protecting the heart from injury and promoting cardiac repair. Our broad unifying hypothesis is that the endogenous natriuretic peptide (NP) system mediates cardiorenal protection and that therapeutic enhancement in experimental and human AMI with exogenous BNP will preserve myocardial structure and function while maintaining renal function. This strategy is based on the biology of BNP that enhances renal function, mediates coronary vasodilatation, reduces myocardial oxygen consumption, suppresses aldosterone release, retards adrenergic activation, induces vascular regeneration, inhibits cardiac fibroblast collagen synthesis and has anti-apoptotic properties. First, we will utilize a murine model of partial proANP gene disruption (Nppa+/-) that has clinical relevance to the recently reported human polymorphism (C664G) that is reported to be characterized by a distruption of the ANP promoter with reduced circulating ANP and risk for ventricular remodeling in human hypertension. This novel genetically altered model has normal cardiac phenotype but demonstrates an exaggerated ventricular hypertrophic and fibrotic response to AMI. In this model with AMI and in wild type (WT) mice we seek to establish cardiorenal protection with 5 days of BNP based therapy. Second, we will extend our research to human AMI investigating the cardiorenal protective properties of 72 hours of BNP therapy initiated at the time of revascularization compared to conventional therapy to preserve myocardial and renal function. Our Specific Aims are as follows: Aim 1: To characterize myocardial structure and function, humoral function and renal function in WT and Nppa+/- mice after AMI; Aim 2: To characterize myocardial structure and function, humoral function and renal function in WT and Nppa+/- mice after AMI in the presence of BNP therapy; and Aim 3: To characterize myocardial structure and function, humoral function and renal function in human AMI in the presence and absence of BNP therapy. For the public, this research may enhance long-term survival after a heart attack. The use of a hormone made in the heart and given at the time of heart attack may help the heart protect and repair itself.

描述（由申请人提供）：我们的目标是确定心脏肽 BNP 是一种新颖且有效的治疗人类急性心肌梗死 (AMI) 的方法，以保护心肌结构和功能。这项高度转化的研究利用了这种小内源性肽的心脏保护和肾脏增强特性，可以保护心脏免受损伤并促进心脏修复。我们广泛的统一假设是，内源性利钠肽 (NP) 系统介导心肾保护，并且用外源性 BNP 增强实验和人类 AMI 的治疗将保留心肌结构和功能，同时维持肾功能。该策略基于BNP的生物学特性，BNP可增强肾功能、介导冠状血管舒张、降低心肌耗氧量、抑制醛固酮释放、延迟肾上腺素能激活、诱导血管再生、抑制心脏成纤维细胞胶原合成并具有抗凋亡特性。首先，我们将利用部分 proANP 基因破坏 (Nppa+/-) 的小鼠模型，该模型与最近报道的人类多态性 (C664G) 具有临床相关性，据报道，其特征是 ANP 启动子破坏，从而降低循环 ANP 和风险用于人类高血压的心室重塑。这种新颖的基因改造模型具有正常的心脏表型，但表现出对 AMI 的过度心室肥厚和纤维化反应。在这个 AMI 模型和野生型 (WT) 小鼠中，我们寻求通过 5 天的 BNP 治疗来建立心肾保护。其次，我们将把我们的研究扩展到人类 AMI，调查血运重建时开始的 72 小时 BNP 治疗与传统治疗相比对保护心肌和肾功能的心肾保护特性。我们的具体目标如下： 目标1：表征AMI后WT和Nppa+/-小鼠的心肌结构和功能、体液功能和肾功能；目标 2：表征 AMI 后接受 BNP 治疗的 WT 和 Nppa+/- 小鼠的心肌结构和功能、体液功能和肾功能；目标 3：在存在和不存在 BNP 治疗的情况下表征人类 AMI 的心肌结构和功能、体液功能和肾功能。对于公众来说，这项研究可能会提高心脏病发作后的长期生存率。使用心脏产生并在心脏病发作时给予的激素可能有助于心脏保护和自我修复。