Cardiac Peptides in Cardiorenal Protection

描述（由申请人提供）：自1981年DeBold及其同事发现心脏激素ANP以来，利钠肽领域取得了显著进展，将新知识转化为心力衰竭（HF）的临床实践。这一新知识强调了心肾机制的重要性，它有助于实现最佳的心血管稳态。其他人和申请人的工作也建立了直接心肌作用，扩大了其治疗潜力，超越肾脏机制。最近，BMP已被评估并批准作为症状性心衰的静脉治疗和心衰的诊断辅助手段。随着新技术的出现，这一领域可以进一步发展，为应用于人类心血管疾病提供额外的知识。我们在实验和人类心衰中的应用的广泛目标是推进心脏肽BNP作为一种新的治疗策略来保护进展性心衰的心脏和肾脏。对BNP的特别关注是基于当前HL36634资助期的重大进展，认识到与ANP相比，BNP在HF中具有更大的利钠作用，而且重要的是其抗醛固酮和抗纤维化特性。申请人的工作也证实了心衰患者独特的血流动力学作用，其中BNP增强舒张功能，降低左室收缩末期和舒张末期容积。此外，对晚期人类心衰的初步研究支持可能存在改变形式的循环BNP，其生物作用降低。因此，我们的具体目标是通过心脏-肾脏机制，通过新型慢性BNP治疗来延缓心衰的进展。我们将采用生理学、基因组学和蛋白质组学的方法，在大型动物模型中进行实验性心衰和早期和晚期人类心衰的研究。我们的具体目的如下：目的1：确定在存在和不存在矿皮质激素过量的情况下，慢性BNP延迟实验性HF的进展。目的2：确定慢性BNP治疗的抗纤维化作用也与心肌负荷无关。目的3：确定早期和晚期人类心衰中循环BNP改变形式的存在。目的4：在体外和体内确定HF患者循环BNP改变形式的生物学作用和结合特性。

DESCRIPTION (provided by applicant): Since the discovery of the cardiac hormone ANP by DeBold and coworkers in 1981, the field of natriuretic peptides has significantly advanced with translation of new knowledge to the clinical practice of heart failure (HF). This new knowledge has underscored the importance of cardio-renal mechanisms that contribute to optimal cardiovascular homeostasis. Work by others and the applicants have also established direct myocardial actions broadening their therapeutic potential beyond renal mechanisms. Most recently, BMP has been evaluated and approved as an intravenous therapy for symptomatic HF and as a diagnostic aid in HF. With the availability of new technologies, this field can be further advanced to provide additional knowledge with application to human cardiovascular disease. The broad objective of our application in experimental and human HF is to advance the cardiac peptide BNP as a novel therapeutic strategy for cardio-renal protection in progressive HF. The special focus on BNP is based upon significant progress during the current HL36634 funding period that recognizes the greater natriuretic action of BNP in HF compared to ANP and also importantly its anti-aldosterone and anti-fibrotic properties. Work by the applicants has also established unique hemodynamic actions in HF in which BNP enhances diastolic function and reduces left ventricular end systolic and diastolic volumes. Further, preliminary studies in advanced human HF support the possible presence of altered forms of circulating BNP with reduced biological action. Our specific goal is therefore to delay the progression of HF with novel chronic BNP based therapy through cardio-renal mechanisms. We will take a physiologic, genomic and proteomic approach in studies in large animal models of experimental HF and early and late stage human HF. Our Specific Aims are as follows: Aim 1: To establish that chronic BNP delays the progression of experimental HF in the presence and absence of mineralocorticoid excess. Aim 2: To determine that the anti-fibrotic action of chronic BNP therapy also is independent of myocardial load. Aim 3: To determine the presence of altered forms of circulating BNP in early and late stage human HF. Aim 4: To determine the biological actions and binding properties of altered forms of circulating BNP in human HF in vitro and in vivo.