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）是医疗保险住院的最常见原因。大约50%的HF患者患有 射血分数低的HF（HFrEF），有治疗方法。另外50%患有HFpEF， （保留射血分数），特征为左心室（LV）无法容纳较大充盈 对心输出量的需求更大。目前，没有治疗HFpEF的方法， 女性占优势（2：1 vs.男性）。值得注意的是，退伍军人事务部已确定为研究重点 妇女退伍军人的健康。HFpEF病理生理学复杂，女性占优势的原因尚不清楚。 然而，研究强烈提示LV纤维化在HFpEF的发展中起作用， 在绝经后妇女中尤为突出。因此，需要识别、评估和开发新的 在前期或后期HFpEF雌性动物模型中靶向纤维化的治疗导致改善的LV功能。 心脏纤维化之前是由炎症失调引起的，其中巨噬细胞是关键。 源自肾脏疾病、肥胖、2型糖尿病和/或 高血压导致促炎细胞因子的激活被认为是导致高血压的可能关键因素。 HFpEF。非特异性抑制炎症以减弱纤维化的药理学方法是 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， 由此失调的过程可以在生理上得到控制，导致纤维化减少。发现 促消退介质，如脂氧素和消退素，以及其受体的鉴定， 甲酰肽受体（FPR），导致了对解决未解决的炎症的新见解。 巨噬细胞表达FPR，当受到刺激时，诱导其M2样极化为促消退表型。 我们在啮齿动物心肌梗死模型中使用FPR激动剂，治疗显著改善了LV 功能和减少非梗死区纤维化。然而，没有研究评估它们在预处理中的潜在用途。 HFpEF的临床女性模型。我们提出：“用FPR激动剂治疗使巨噬细胞极化， 在动物模型中限制不利的左心室重构和纤维化的促消退表型 女性HFpEF，导致心腔功能改善”。目标1将测试口服FPR是否 激动剂（化合物43）对早期HFpEF的雌性动物模型预防纤维化的发展 从而保持最佳心肌材料特性， 和收缩功能。目的2如果将FPR激动剂口服给药至HFpEF的雌性动物模型， 肾损伤的复合改善组织纤维化，从而保护最佳心肌材料 性质，从而改善左心室舒张和收缩功能。目的3：如果口服给药 FPR激动剂对早期或复合HFpEF的雌性动物模型的促肾上腺皮质激素释放激素的血液水平正常化 炎症细胞因子和触发巨噬细胞的极化到促消退表型。我们还将 对浸润性白细胞群体以及巨噬细胞衍生的 条件培养基处理培养的心脏成纤维细胞，以评估其对细胞表型的影响。