Cardiac Peptides in Cardiorenal Protection

描述（由申请人提供）：自DeBold及其同事于1981年发现心脏激素ANP以来，利钠肽领域随着新知识转化为心力衰竭（HF）的临床实践而取得了显著进展。这一新的知识强调了心肾机制的重要性，有助于最佳的心血管稳态。其他人和申请人的工作也建立了直接的心肌作用，扩大了其治疗潜力，超越了肾脏机制。最近，BMP已被评估并批准作为症状性HF的静脉内治疗和HF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，为人类心血管疾病的应用提供更多的知识。我们在实验和人类HF中应用的广泛目标是推进心脏肽BNP作为进行性HF心肾保护的新治疗策略。对BNP的特别关注是基于当前HL 36634资助期间的重大进展，该研究认识到BNP在HF中的利钠作用大于ANP，而且其抗醛固酮和抗纤维化特性也很重要。申请人的工作还建立了HF中独特的血液动力学作用，其中BNP增强舒张功能并降低左心室收缩末期和舒张末期容积。此外，对晚期人HF的初步研究支持可能存在生物作用降低的循环BNP改变形式。因此，我们的具体目标是通过心肾机制，采用基于BNP的新型慢性治疗来延缓HF的进展。我们将采用生理学、基因组学和蛋白质组学方法研究实验性HF和早期和晚期人类HF的大型动物模型。我们的具体目的如下：目的1：确定在盐皮质激素过量存在和不存在的情况下，慢性BNP延迟实验性HF的进展。目的2：确定长期BNP治疗的抗纤维化作用也不依赖于心肌负荷。目的3：确定在早期和晚期人类HF中循环BNP的改变形式的存在。目的4：在体外和体内确定人HF中循环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.