Cardiovascular Peptides and Myocardial Infarction

描述(申请人提供)：我们的目标是确定心脏多肽BNP是一种新的、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。这项高度翻译的研究利用了这种小的内源性多肽在保护心脏免受损伤和促进心脏修复方面的心脏保护和肾脏增强特性。我们广泛的统一假设是，内源性钠尿肽(NP)系统介导了心肾保护，外源性BNP对实验性和人类急性心肌梗死的治疗增强将在维持肾功能的同时保护心肌结构和功能。这一策略基于BNP的生物学功能，BNP具有增强肾功能、介导冠状动脉扩张、降低心肌耗氧量、抑制醛固酮释放、延缓肾上腺素能激活、诱导血管再生、抑制心脏成纤维细胞胶原合成和抗细胞凋亡的特性。首先，我们将利用部分proANP基因中断的小鼠模型(NPPA+/-)，该模型与最近报道的人类多态(C664G)具有临床相关性，据报道，C664G多态的特征是ANP启动子缺失，循环ANP减少，人类高血压患者发生心室重构的风险增加。这一新的基因改变的模型具有正常的心脏表型，但显示了对急性心肌梗死的夸大的心肌肥厚和纤维化反应。在这个急性心肌梗死模型和野生型(WT)小鼠中，我们寻求通过基于BNP的5天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急性心肌梗死，研究在血运重建时开始的72小时BNP治疗与传统治疗相比对心肾保护特性的影响。我们的具体目标如下：目的1：研究WT和NPPA+/-小鼠急性心肌梗死后的心肌结构和功能、体液功能和肾功能；目的2：研究BNP治疗对WT和NPPA+/-小鼠急性心肌梗死后心肌结构和功能、体液功能和肾功能的影响；目的3：研究BNP治疗前后人急性心肌梗死的心肌结构和功能、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存活率。在心脏病发作时使用在心脏中制造的荷尔蒙可以帮助心脏保护和修复自身。

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.