Beneficial Effects of FPR Agonists on an Animal Model of Early Stage Heart Failure with Preserved Ejection Fraction

心力衰竭(HF)是医疗保险住院的最常见原因。大约50%的心力衰竭患者患有 有治疗方法的低射血分数心衰(HFrEF)。另外50%的人患有HFpEF， (保留的射血分数)特征是左心室(LV)无法容纳更大的充盈 随着对心输出量的更大需求而增加容量。目前，HFpEF和研究还没有可用的治疗方法 表现出女性占优势(2：1对男性)。值得注意的是，退伍军人管理局已将其确定为研究重点 女退伍军人的健康。HFpEF的病理生理机制复杂，女性占优势的原因尚不清楚。 然而，研究强烈表明，左室纤维化在HFpEF的发展过程中起着重要作用。 在绝经后妇女中加重。因此，需要对小说进行识别、评估和开发 针对纤维化的HFpEF雌性动物模型前期或后期的治疗可改善左心功能。 心脏纤维化是由巨噬细胞起关键作用的失调炎症引起的。 肾脏疾病、肥胖、2型糖尿病和/或 高血压导致促炎细胞因子的激活被确定为可能的关键因素 HFpEF。非特异性抑制炎症以减轻纤维化的药物方法有 耐受性差。然而，炎症的选择性和靶向调节已经成为一个概念 从而可以从生理上控制这一失调的过程，从而减少纤维化。这一发现 脂氧素和溶血素等促拆分介质及其受体的鉴定 甲酰肽受体(FPR)，为解决未解决的炎症提供了新的见解。 巨噬细胞表达FPR，当受到刺激时，诱导其M2样极化到支持分解的表型。 我们在心肌梗死的啮齿动物模型中使用了FPR激动剂，在这种模型中，治疗显著改善了左心室 功能，减少非梗死区纤维化。然而，还没有研究评估它们在预激反应中的潜在用途。 HFpEF的临床女性模型。我们认为：“用fpr激动剂治疗使巨噬细胞极化为 模拟动物模型中限制不良左心室重构和纤维化的预分辨表型 HFpEF在女性中的应用，导致心腔功能的改善“。目标1将测试口服FPR 激动剂(化合物43)对早期HFpEF雌性动物模型的预防作用 从而保存最佳的心肌材料特性，从而改善左心室的舒张期 和收缩功能。目的2口服FPR激动剂对HFpEF雌性动物模型的影响 复合肾脏损伤可改善组织纤维化，从而保存最佳的心肌材料 因此，改善了左心室的舒缩功能。目标3如果口服阿司匹林 FPR激动剂用于早期雌性动物模型或复合HFpEF使血PRO水平正常化 炎性细胞因子，并触发巨噬细胞的极化到支持分解的表型。我们还将 对浸润性白细胞和来源的巨噬细胞进行更广泛的表征 条件培养液处理培养的心脏成纤维细胞以评估其对细胞表型的影响。

Heart failure (HF) is the most common cause of Medicare hospitalizations. About 50% of HF patients suffer from HF with low ejection fraction (HFrEF) for which there are treatments. The other 50% suffer from HFpEF, (preserved ejection fraction) characterized by the inability of the left ventricle (LV) to accommodate larger filling volumes upon greater demands in cardiac output. Currently, no treatments are available for HFpEF and studies demonstrate a female predominance (2:1 vs. men). Noteworthy, the VA has identified as a research priority Women Veteran’s health. HFpEF pathophysiology is complex and the cause for female predominance is unclear. However, studies strongly suggest a role for LV fibrosis in the development of HFpEF which, appears accentuated in post-menopausal women. Thus, there is a need to identify, evaluate and develop novel treatments in pre- or later stage HFpEF female animal models targeting fibrosis leading to improved LV function. Cardiac fibrosis is preceded and orchestrated by dysregulated inflammation where macrophages are key. Systemic inflammation derived from the presence of kidney disease, obesity, type 2 diabetes and/or hypertension leading to the activation of pro-inflammatory cytokines was identified as a likely key contributor to HFpEF. Pharmacologic approaches that non-specifically inhibit inflammation so as to attenuate fibrosis, are poorly tolerated. However, selective and targeted modulation of inflammation has emerged as a concept whereby the dysregulated process may be physiologically controlled leading to reduced fibrosis. The discovery of pro-resolution mediators such as lipoxins and resolvins as well as the identification of their receptors such as the formyl peptide receptor (FPR), has led to new insights towards addressing unresolved inflammation. Macrophages express FPR that when stimulated, induce their M2 like polarization to a pro-resolution phenotype. We utilized FPR agonists in rodent models of myocardial infarction where treatment significantly improves LV function and reduces non-infarcted area fibrosis. However, no studies have assessed their potential use in pre- clinical female models of HFpEF. We propose that: “Treatment with FPR agonists polarizes macrophages to a pro-resolution phenotype limiting adverse left ventricular remodeling and fibrosis in animal models mimicking HFpEF in women, leading to improved chamber function”. Aim 1 will test if the oral administration of an FPR agonist (compound 43) to a female animal model of early stage HFpEF prevents the development of fibrosis leading to the preservation of optimal myocardial material properties and thus, improved left ventricular diastolic and systolic function. Aim 2 if the oral administration of an FPR agonist to a female animal model of HFpEF compounded by renal injury ameliorates tissue fibrosis leading to the preservation of optimal myocardial material properties and thus, improved left ventricular diastolic and systolic function. Aim 3 if the oral administration of an FPR agonist to female animal models of early stage or compounded HFpEF normalizes blood levels of pro- inflammatory cytokines and triggers the polarization of macrophages to a pro-resolution phenotype. We will also perform a broader characterization of the infiltrating leucocyte population as well as macrophage derived conditioned media treatment of culture cardiac fibroblasts to assess its effects on cell phenotype.