Novel Peptide Therapeutics for Cardiorenal Protection in Heart Failure

项目总结 我们提出了治疗心力衰竭(HF)的创新性心肾保护性多肽疗法。研究将会 研究NPA7，一种新的多价和一流的多肽，由申请者设计，共同瞄准两个 生物途径。这两个靶点是利钠肽/颗粒鸟苷酸环化酶-A。 受体/cGMP和血管紧张素1-7/MASR/cAMP系统。我们假设NPA7介导心肾功能 通过这些互补途径的保护作用，并具有超越PGC-A和 单独激活MASR。重要的是，我们还假设NPA7在一种 过度活跃的肾素-血管紧张素-醛固酮系统(RAAS)如NPA7可能抑制醛固酮 产生/释放、拮抗AT1、抑制肾素和抑制肾脏血管紧张素原(AGT)。 对实验性心衰的初步研究表明，除了钠滞留和充血之外，还有激活 肾脏中有害的分子通路导致炎症、细胞凋亡和纤维化，这可能导致 肾脏功能和结构进行性恶化，预后不良。而多因素机制可能 血管紧张素II(Ang II)参与慢性心衰肾脏结构和功能的进行性损害，是一种 基础调解人。在这里，NPA7可能通过PGC-A和MASR激活互补的RAAS抑制和 增强心肾保护的拮抗机制。我们还提出了尿液的概念 促血管紧张素转换酶(UAGT)可作为一种新的肾脏病理生理标志物 肾内RAAS激活，不依赖循环RAAS。事实上，一个主要的长期目标是 UAGT作为肾内RAAS新的尿标记物辅助高危人群的研究 可能受益于NPA7治疗的心衰患者。目的1：测定丹参对心肾的保护作用 NPA7在体外培养的人肾小管细胞、心肌细胞、肾成纤维细胞和心肌成纤维细胞中的表达。目标2： 确定慢性NPA7治疗的心脏肾保护和肾内RAAS抑制特性 慢性心力衰竭的大型动物模型表现为心肌泵衰竭，肾血流灌注减少 与ACEI相比，肾内充血和肾内RAAS明显激活。目标3：测定体内uAGT水平 高危慢性心衰患者与肾功能损害的关系及其对未来的预测价值 心力衰竭住院和死亡。

PROJECT SUMMARY We advance innovative cardiorenal protective peptide therapeutics for heart failure (HF). Studies will investigate NPA7, a novel, multivalent and first-in-class peptide, engineered by the applicants to co-target two biological pathways. These two targets are the natriuretic peptide/particulate guanylyl cyclase-A receptor/cGMP and Angiotensin1-7/MasR/cAMP systems. We hypothesize that NPA7 mediates cardiorenal protective properties via these complementary pathways and has synergistic actions beyond pGC-A and MasR activation alone. Importantly, we also hypothesize that NPA7 is highly effective in a state of an overactive intrarenal renin-angiotensin-aldosterone system (RAAS) as NPA7 may suppress aldosterone production/release, antagonize AT1, suppress renin and inhibit angiotensinogen (AGT) in the kidney. Preliminary studies in experimental HF reveal that beyond sodium retention and congestion, there is activation of deleterious molecular pathways in the kidney for inflammation, apoptosis, and fibrosis, which may result in progressive worsening renal function and structure with poor outcomes. While multifactorial mechanisms may be involved in progressive renal structural and functional impairment in chronic HF, Angiotensin II (ANG II) is a fundamental mediator. Here NPA7, via pGC-A and MasR, may activate complementary RAAS inhibiting and antagonizing mechanisms with amplified cardiorenal protection. We also advance the concept that urinary AGT (uAGT), which drives the renal generation of ANG II, may serve as a novel pathophysiological biomarker for intrarenal RAAS activation, independent of circulating RAAS. Indeed, a major long-term goal is the development of uAGT as a novel urinary biomarker for intrarenal RAAS to aid in the identification of high-risk HF patients that may benefit from NPA7 therapy. Aim 1: Determine the cardiorenal protective properties of NPA7 in human renal tubular cells, cardiomyocytes and renal and myocardial fibroblasts in vitro. Aim 2: Determine cardiorenal protective and intrarenal RAAS suppressing properties of chronic NPA7 therapy in a large animal model of chronic HF that exhibits myocardial pump failure, reduced renal perfusion with congestion and markedly activated intrarenal RAAS compared to ACEi. Aim 3: Determine uAGT levels in high-risk chronic HF patients and its association with impaired renal function and its predictive power for future HF hospitalization and death.