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

FPR 激动剂对射血分数保留的早期心力衰竭动物模型的有益作用

• 批准号: 10580246
• 负责人: Francisco J Villarreal
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580246
• 关键词: Address; Adverse event; Age; Age Years; Agonist; Animal Model; Animals; Area; Attenuated; Blood; Cardiac; Cardiac Output; Cells; Clip; Collagen; Complex; Data; Deposition; Development; Diffuse; Disease; EFRAC; Endocardium; Exhibits; Exposure to; Female; Fibroblasts; Fibrosis; Fructose; Functional disorder; Future; Goals; Health; Heart; Heart Diseases; Heart failure; Hospitalization; Hypertension; Inflammation; Inflammatory; Injury to Kidney; Kidney; Kidney Diseases; Lead; Left; Left Ventricular Remodeling; Left ventricular structure; Leucocytic infiltrate; Lipoxins; Macrophage; Mediator; Medicare; Modeling; Mus; Myocardial; Myocardial Infarction; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral Administration; Ovariectomy; Pathway interactions; Patients; Phase I Clinical Trials; Phenotype; Physiological; Play; Population; Post-Traumatic Stress Disorders; Postmenopause; Process; Property; Rattus; Relaxation; Reporting; Research; Research Priority; Resolution; Risk Factors; Rodent Model; Role; Severities; Steroids; Stress; Testing; Therapeutic; Tissues; Ventricular; Veterans; Weight Gain; Woman; Work; aged; blood pump; coronary fibrosis; cytokine; drinking water; experience; fMet-Leu-Phe receptor; improved; improved outcome; insight; interest; male; men; military veteran; new therapeutic target; novel; novel therapeutic intervention; pharmacologic; polarized cell; pre-clinical; preservation; prevent; receptor; statistics; systemic inflammatory response; tool

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.

心力衰竭 (HF) 是 Medicare 住院的最常见原因。大约 50% 的心力衰竭患者患有 低射血分数心衰 (HFrEF) 有治疗方法。另外 50% 患有 HFpEF， （射血分数保留）的特点是左心室 (LV) 无法容纳更大的充盈 体积对心输出量的更大需求。目前，尚无针对 HFpEF 的治疗方法和研究 表现出女性优势（2:1 与男性）。值得注意的是，VA 已将其确定为研究重点 女退伍军人的健康。 HFpEF 病理生理学很复杂，女性占主导地位的原因尚不清楚。 然而，研究强烈表明左心室纤维化在 HFpEF 的发展中发挥着作用，这似乎 在绝经后妇女中尤为突出。因此，需要识别、评估和开发新颖的 在 HFpEF 雌性动物模型前期或后期进行针对纤维化的治疗，从而改善左心室功能。 心脏纤维化是由炎症失调引起的，其中巨噬细胞是关键。 因肾脏疾病、肥胖、2 型糖尿病和/或 导致促炎细胞因子激活的高血压被认为是可能的关键因素 HFpEF。非特异性抑制炎症以减轻纤维化的药理学方法是 耐受性差。然而，选择性和有针对性的炎症调节已成为一个概念 由此，失调的过程可以在生理上得到控制，从而减少纤维化。发现 促分解介质（如脂氧素和分解素）及其受体的鉴定，如 甲酰肽受体（FPR）为解决未解决的炎症带来了新的见解。 巨噬细胞表达 FPR，当受到刺激时，会诱导其 M2 样极化，形成亲分辨率表型。 我们在啮齿动物心肌梗塞模型中使用 FPR 激动剂，治疗可显着改善左心室 (LV) 功能并减少非梗塞区域纤维化。然而，没有研究评估它们在预治疗中的潜在用途。 HFpEF 的临床女性模型。我们建议：“FPR 激动剂治疗使巨噬细胞极化为 模拟动物模型中促消退表型限制不良左心室重塑和纤维化 女性中的 HFpEF，从而改善心室功能”。目标 1 将测试口服 FPR 是否有效 早期 HFpEF 雌性动物模型中的激动剂（化合物 43）可预防纤维化的发展 导致保留最佳的心肌材料特性，从而改善左心室舒张压 和收缩功能。目标 2：向 HFpEF 雌性动物模型口服 FPR 激动剂 加上肾损伤可改善组织纤维化，从而保存最佳的心肌材料 特性，从而改善左心室舒张和收缩功能。目标 3 如果口服 FPR 激动剂对早期雌性动物模型或复合 HFpEF 可使血中亲- 炎症细胞因子并触发巨噬细胞极化为促消退表型。我们还将 对浸润白细胞群以及巨噬细胞衍生的细胞进行更广泛的表征 对培养的心脏成纤维细胞进行条件培养基处理，以评估其对细胞表型的影响。