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是人类急性心肌梗死（AMI）的一种新颖有效的疗法，可保留心肌结构和功能。这项高度转化的研究利用了这种小型和内源性肽的心脏保护和肾脏增强特性，以保护心脏免受损伤和促进心脏修复。我们广泛的统一假设是，内源性亚钠肽（NP）系统介导心脏保护，并且具有外源性BNP的实验和人类AMI的治疗性增强将在维持肾功能时保持心肌结构和功能。该策略基于BNP的生物学，从而增强了肾功能，介导冠状动脉血管扩张，减少心肌氧的消耗量，抑制醛固酮释放，延迟肾上腺素能激活，诱导血管再生，抑制心脏成纤维成纤维组合胶原蛋白的合成和具有抗抗磷酸抗性物质。首先，我们将利用与最近报道的人类多态性（C664G）具有临床相关性的部分proanp基因破坏（NPPA +/-）模型，据报道，该模型的特征是ANP促进者的特征是ANP促进剂的循环ANP降低和人体抑制性降低的人体抑制作用的风险。这种新型的遗传改变模型具有正常的心脏表型，但表现出对AMI的夸张心室肥厚和纤维化反应。在使用AMI和野生型（WT）小鼠的模型中，我们试图通过基于BNP的5天治疗来建立心脏保护。其次，与常规疗法相比，我们将研究研究在血运重建时开始的72小时BNP治疗的心脏保护特性，以保留心肌和肾功能。我们的具体目的如下：目标1：表征心肌结构和功能，AMI后WT和NPPA +/-小鼠中的体液功能和肾功能；目标2：在BNP治疗的情况下，在AMI之后，在WT和NPPA +/-小鼠中表征心肌结构和功能，体液功能和肾功能；和目标3：在BNP治疗的存在和不存在的情况下，为了表征人AMI的心肌结构和功能，体液功能和肾功能。对于公众来说，这项研究可能会在心脏病发作后增强长期生存。在心脏病发作时使用的激素并在心脏病发作时使用可能有助于心脏保护和修复。