Resolvin D1 resolves inflammation in metabolic stress associated HFpEF

Resolvin D1 解决代谢应激相关 HFpEF 中的炎症

• 批准号: 10533087
• 负责人: Suresh Selvaraj Palaniyandi
• 金额: $ 24.49万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533087
• 关键词: Accounting; Address; Age-Months; Animal Model; Apoptosis; Apoptotic; Applied Research; Attenuated; Automobile Driving; Binding; Biometry; Blood; Bone Marrow; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Nucleus; Cells; Chronic; Clinical; Complex; Coronary; Development; Diabetes Mellitus; Diagnosis; EFRAC; Exercise Tolerance; Exudate; FPR2 gene; Failure; Fibrosis; Functional disorder; Gene Expression; Genes; Goals; Heart; Heart failure; Homeostasis; Hospitalization; Human; Hypertension; Hypertrophy; Incidence; Infiltration; Inflammation; Inflammatory; Innovative Therapy; Leukocytes; Lipoxins; MERTK gene; Macrophage Activation; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic stress; Modeling; Monitor; Mus; Myocardial; Myocarditis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Oxidative Stress; Pathogenesis; Patients; Phenotype; Physiological; Process; Proto-Oncogenes; Public Health; Published Comment; Pump; Quality of life; Research; Resolution; Signal Pathway; Spleen; Suggestion; Surface; Testing; Therapeutic; Therapeutic Effect; Tissues; Treatment Failure; Tyrosine-Kinase Oncogenes; United States National Institutes of Health; Vascular Endothelial Cell; base; cell type; chronic inflammatory disease; comorbidity; coronary fibrosis; cytokine; db/db mouse; drug discovery; efficacy testing; fundamental research; heart function; improved; innovation; interest; macrophage; molecular marker; monocyte; mortality; preservation; prophylactic; receptor; reduce symptoms; response; subcutaneous; systemic inflammatory response; transcriptome sequencing; treatment strategy

Abstract: Current heart failure (HF) treatments are not effective in heart failure with preserved ejection fraction (HFpEF), despite the fact that 50% of all HF cases in the USA are HFpEF. Patients with HFpEF have high incidences of mortality, hospitalizations, and a poor quality of life. Thus, there is a critical need to find suitable therapeutic strategies for patients with HFpEF, based on pathophysiology. However, HFpEF pathophysiology is complex due to systemic comorbidities like obesity, diabetes, and hypertension. Systemic inflammation from such metabolic diseases a.k.a metabolic inflammation is key in driving the HFpEF pathogenesis. Chronic inflammation occurs due to the imbalance between proinflammation and resolution, including in HFpEF. Thus, we plan to develop suitable innovative therapies on strategies to improve the resolution of inflammation to curtail HFpEF progression. Resolution is an orchestrated process carried out by the actions of specialized pro-resolving mediators (SPMs) such as resolvins, lipoxins and maresins (secreted in inflammatory exudates). SPMs bind to their specific receptors to elicit tissue homeostasis by reducing further infiltration of leukocytes and increasing efferocytosis, i.e., clearing of cardiac apoptotic cells. Resolvin D1 (RvD1), one of the potent SPMs, acts via its receptor, formyl-peptide receptor-2 (FPR2) and decreases pro-inflammatory, pro-fibrotic gene expression and cytokines and promote efferocytosis. These effects are mediated via polarizing blood/bone marrow derived monocytes and splenic/myocardial macrophages from proinflammatory to pro- resolving phenotypes, that express FPR2. However, the effect of RVD1 in HFpEF, a big clinical issue with unresolved inflammation, has not been studied. The primary goal of our R21 proposal is to test the efficacy of RvD1 as a potential therapy for HFpEF driven by metabolic diseases. Thus, our proposal meets the goal of NIH’s Special Interest (NOSI-ES-20-018) notice: Promoting Fundamental and Applied Research in Inflammation Resolution. Mimicking all the features of human HFpEF in an animal model is challenging. However, db/db mice, a model of obesity mediated T2DM, recapitulate the major features of HFpEF; hence, we chose to employ db/db mice for the proposed studies. Our hypothesis is that RvD1 resolves systemic and cardiac inflammation by reprogramming monocytes/macrophages and thereby ameliorating metabolic stress associated with HFpEF. We propose two specific aims to test our hypothesis: 1) To determine the prophylactic effect of RvD1; and 2) To determine the therapeutic effect of RvD1. We will treat the mice systemically with RvD1 before (for prophylactic effects) and after (for therapeutic effects) onset of HFpEF. We will focus on RvD1 mediated increase in efferocytosis of dying cardiac cells i.e., coronary vascular endothelial cells (aim 1) and cardiomyocytes (aim 2) as its mechanism of action. The expected outcome of this project is to establish RvD1 as a therapeutic option for HFpEF, a chronic inflammatory disease with no suitable treatments. Our innovative idea to target resolution of metainflammation can move the drug discovery research for HFpEF forward.

摘要：当前的心力衰竭（HF）治疗在保留的射血中对心力衰竭无效 分数（HFPEF）提出的事实是，美国所有HF病例中有50％均为HFPEF。 HFPEF患者有 高死亡率，住院和生活质量差。那是迫切需要找到的 基于病理生理学的HFPEF患者的合适治疗策略。但是，HFPEF 由于肥胖，糖尿病和高血压等全身性合并症，病理生理学很复杂。系统性 此类代谢疾病的炎症也是A代谢感染是驱动HFPEF的关键 发病。慢性炎症是由于促进症和解决方案之间的不平衡而发生的 包括HFPEF。这，我们计划开发出适当的创新疗法，以改善策略 解决炎症减少HFPEF进展。解决方案是由 专业支持的促进介质（SPM）的行动，例如Resolvins，Lipoxins和Maresins（分泌在 炎症渗出液）。 SPM通过进一步降低而与其特定受体结合，从而引起组织体内稳态 白细胞浸润和增加的肿瘤病，即心脏凋亡细胞清除。 Resolvin D1（RVD1）， 通过其受体，甲基肽受体-2（FPR2）起作用的潜在SPM之一，可降低促炎的性， 促纤维化基因表达和细胞因子并促进效率。这些效果是通过偏振介导的 血/骨髓衍生的单核细胞和脾脏/心肌巨噬细胞从促炎到促疾病 解决表型，表达FPR2。但是，RVD1在HFPEF中的影响，这是一个很大的临床问题 未解决的炎症尚未研究。我们R21提案的主要目标是测试 RVD1是由代谢疾病驱动的HFPEF的潜在疗法。那，我们的建议符合NIH的目标 特殊兴趣（Nosi-ES-20-018）通知：促进炎症的基本和应用研究 解决。挑战模仿动物模型中人类HFPEF的所有特征。但是，DB/DB小鼠， 肥胖介导的T2DM模型，概括了HFPEF的主要特征。因此，我们选择使用DB/DB 拟议研究的小鼠。我们的假设是RVD1通过 重编程单核细胞/巨噬细胞，从而改善与HFPEF相关的代谢应激。我们 提案两个特定的目的是检验我们的假设：1）确定RVD1的预防作用；和2）到 确定RVD1的治疗作用。在预防性之前，我们将用RVD1系统地对小鼠进行系统处理 效果）和（用于治疗效应）HFPEF的开始。我们将专注于RVD1介导的增加 垂死的心脏细胞的肿瘤病，即冠状动脉血管内皮细胞（AIM 1）和心肌细胞（AIM 2） 作为其作用机理。该项目的预期结果是建立RVD1作为治疗选择 对于HFPEF，一种没有合适治疗的慢性炎性疾病。我们的创新想法是针对解决方案 元炎症可以推动HFPEF前进的药物发现研究。