A new large pre-clinical model of aging-related heart failure: a platform to develop new therapies for HFpEF

心力衰竭伴保留射血分数(HFpEF)是老年人心力衰竭的主要形式，也是最常见的心力衰竭之一 心脏病领域最大的未得到满足的需求。心血管衰老是一个复杂的过程，由危险因素、生物学因素 变量(例如，性别)，以及诸如慢性肾脏疾病(CKD)等普遍存在的共病，这些因素都会导致 高频的发展。慢性肾脏病是一种影响近40%的美国成年人的疾病，65岁≥和HFpEF出现在 超过50%的CKD患者。然而，关于衰老对CKD-HFpEF病理生理学的影响的了解有限 而模型的缺乏要求采取新的策略来对抗CKD患者的心功能恶化。 我们是唯一有资格满足这些需求的人，因为1)我们在幼猪身上开发了一种左侧CKD模型 心脏重塑和舒张期功能不全--重述人类高场心脏射血分数。2)心功能不全和 CKD-HFpEF模型重构显示心脏血管内皮生长因子显著减少 (血管内皮生长因子)的表达，与先前对老化心脏的研究一致。3)我们开发的药物传递载体是基于 弹性蛋白样多肽(ELP)，并显示了它们向肾脏输送治疗药物的有效性，包括血管内皮生长因子。在……里面 此外，我们建立了一个ELP文库，根据它们的分子量可以靶向不同的器官，包括 心。然而，ELP从未被用于心脏治疗。4)无偏分析(已发布的数据库) 幼年CKD-HFpEF模型显示心脏异常与心脏表观遗传学和 血管内皮生长因子相关基因的miRNA修饰，血管生成信号的改变，以及心脏微血管稀疏。 这一创新的R21提案的前提是多方面的：1)我们将开发第一个型号的HFpEF 来概括人类衰老的HFpEF的表型。这一模式还将促进 以前所未有的方式将年龄和性别作为生物变量进行研究。2)我们将首次测试一个 减少心脏微血管稀疏的治疗策略，这是心功能不全的一个重要决定因素 通过使用基于ELP的治疗性血管生成来靶向血管生成信号的HFpEF。最后，我们将设置 通过明确心脏驱动的血管内皮生长因子下调机制为衰老HFpEF的新疗法奠定基础 MicroRNA(MiRNA)与表观遗传调控。 目的1：建立第一个正常大鼠肺间质纤维化模型 老猪。 这些研究将确定HFpEF老化的病理途径，并提供一个新的合适的平台 以翻译的方式指导新的治疗策略的开发。 目标2：下调血管内皮生长因子 在衰老过程中，信号转导导致心脏微血管稀疏和HFpEF。 这些研究将机械地 明确血管内皮生长因子在正常衰老心脏中的作用，为新的针对衰老的靶向治疗奠定基础 HFpEF。通过识别血管内皮生长因子相关基因心脏信号改变的机制，我们将为 探索新的治疗方法。该建议通过开发老化HFpEF的新模型来确保创新 并通过为HFpEF的新治疗策略建立机制基础，这将导致 这是一种范式转变，与NIH-NIA从板凳到床边的战略使命相一致。

Heart failure with preserved ejection fraction (HFpEF) is the predominant form of HF in the elderly and one of the largest unmet needs in cardiology. Cardiovascular aging is a complex process crafted by risk factors, biological variables (e.g., sex), and prevalent comorbidities like chronic kidney disease (CKD) that contribute to the development of HF. CKD is a disease that affects almost 40% of US adults ≥65 years and HFpEF is present in over 50% of CKD patients. However, limited knowledge about the impact of aging on CKD-HFpEF pathophysiology and the lack of models calls for efforts for new strategies to counteract the deterioration of cardiac function in CKD. We are uniquely qualified to address these needs since 1) We developed in juvenile pigs a model of CKD with left ventricular remodeling and diastolic dysfunction that recapitulates human HFpEF. 2) Cardiac dysfunction and remodeling in the CKD-HFpEF model show a significant reduction in cardiac vascular endothelial growth factor (VEGF) expression, in line with prior research on aging hearts. 3) We developed drug-delivery vectors based on elastin-like polypeptides (ELP) and showed their efficacy to deliver therapeutics to the kidney, including VEGF. In addition, we built a library of ELPs that based on their molecular weight can target different organs, including the heart. However, ELPs have never been used for cardiac therapies. 4) Unbiased analysis (published database) in the juvenile CKD-HFpEF model showed that cardiac abnormalities are associated with cardiac epigenetic and miRNA modifications of VEGF-related genes, altered angiogenic signaling, and cardiac microvascular rarefaction. The premise underlying this innovative R21 proposal is multi-fold: 1) We will develop the first model of HFpEF in normally aged pigs to recapitulate the phenotype of aging HFpEF in humans. This model will also foster the study of age and sex as biological variables in an unprecedented fashion. 2) We will test, for the first time, a therapeutic strategy to abate cardiac microvascular rarefaction, an important determinant of cardiac dysfunction in HFpEF by targeting VEGF angiogenic signaling using ELP-based therapeutic angiogenesis. Finally, we will set the foundation for new therapies in aging HFpEF by defining mechanisms of VEGF downregulation driven by cardiac microRNA (miRNA) and epigenetic modulation. Aim 1: Development of the first model of HFpEF in a normally aged swine. These studies will identify pathological pathways in aging HFpEF and offer a new suitable platform to guide the development of new therapeutic strategies in a translational fashion. Aim 2: Downregulation of VEGF signaling leads to cardiac microvascular rarefaction and HFpEF in aging. These studies will mechanistically define the role of VEGF in the normally aged heart and build the foundation for a new targeted therapy in aging HFpEF. By discerning mechanisms of altered cardiac signaling of VEGF-related genes, we will set the stage to explore new treatments. This proposal assures innovation by both developing a new model of aging HFpEF and by establishing the mechanistic foundation for new therapeutic strategies for HFpEF, which will result in a paradigm shift that aligns with the bench-to-bedside strategic mission of the NIH-NIA.