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：目前的心力衰竭治疗方法对射血功能保留的心力衰竭并不有效。 分数(HFpEF)，尽管美国50%的HF病例是HFpEF。患有HFpEF的患者有 高死亡率、高住院率和低生活质量。因此，迫切需要找到 以病理生理学为基础，为HFpEF患者制定合适的治疗策略。然而，HFpEF 由于肥胖、糖尿病和高血压等全身共病，病理生理学是复杂的。系统性 这些代谢性疾病引起的炎症也就是代谢性炎症是推动HFpEF的关键 发病机制。慢性炎症的发生是由于前炎症和消退之间的不平衡， 包括在HFpEF中。因此，我们计划开发合适的创新疗法，以改善 消退炎症以抑制HFpEF进展。解决方案是一个经过精心安排的过程，由 专门化的促分解介质(SPM)的作用，如分解素、脂氧素和松脂(分泌于 炎性渗出物)。SPM与其特定的受体结合，通过进一步减少 白细胞的渗入和增多的胞吐，即清除心肌细胞的凋亡。分解蛋白D1(Rvd1)， 一种有效的SPM，通过其受体甲酰肽受体-2(FPR2)发挥作用，减少促炎作用， 促进肝纤维化基因表达和细胞因子，促进胞吐。这些效应是通过偏振来调节的。 血/骨髓来源的单核细胞和脾/心肌巨噬细胞从促炎到促炎症 解析表达FPR2的表型。然而，RvD1在HFpEF中的作用，这是一个很大的临床问题 未解决的炎症，还没有研究过。我们R21提案的主要目标是测试 Rvd1可作为代谢性疾病所致HFpEF的潜在治疗方法。因此，我们的建议符合美国国立卫生研究院的目标 特别关注(NOSI-ES-20-018)通告：促进炎症的基础和应用研究 决心。在动物模型中模仿人类HFpEF的所有特征是具有挑战性的。然而，db/db小鼠， 肥胖介导的2型糖尿病模型，概括了HFpEF的主要特征；因此，我们选择使用db/db 拟进行研究的小白鼠。我们的假设是，Rvd1通过以下方式解决全身和心脏炎症 重新编程单核/巨噬细胞，从而改善与HFpEF相关的代谢应激。我们 提出两个具体目标来验证我们的假设：1)确定Rvd1的预防效果；2) 测定Rvd1的治疗效果。我们将对小鼠进行系统的Rvd1治疗(用于预防 效果)和在HFpEF开始后(为了治疗效果)。我们将重点关注Rvd1介导的 濒临死亡的心肌细胞，即冠状动脉血管内皮细胞(Aim 1)和心肌细胞(Aim 2)的胞吐作用 作为它的作用机制。该项目的预期结果是将Rvd1确立为一种治疗选择 对于HFpEF，一种慢性炎症性疾病，没有合适的治疗方法。我们的创新想法是以目标为目标 可以推动HFpEF的药物发现研究向前发展。