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: 10704156
• 负责人: Suresh Selvaraj Palaniyandi
• 金额: $ 15.88万
• 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/10704156
• 关键词: Accounting; Acting Out; Address; Age Months; Animal Model; Apoptosis; Apoptotic; Applied Research; Attenuated; Automobile Driving; Binding; Biometry; Blood; Blood Vessels; Bone Marrow; Cardiac; Cardiac Myocytes; Cardiovascular system; Cells; Chronic; Clinical; Complex; Coronary; Development; Diabetes Mellitus; Diagnosis; EFRAC; Exercise Tolerance; Exudate; FPR2 gene; Fibrosis; Functional disorder; Gene Expression; Genes; Goals; Heart; Heart Research; Heart failure; Homeostasis; Hospitalization; Human; Hypertension; Hypertrophy; Incidence; Infiltration; Inflammation; Inflammatory; Innovative Therapy; Leucocytic infiltrate; Lipoxins; MERTK gene; Macrophage; Macrophage Activation; Measures; Mediating; Mediator; Metabolic; Metabolic Diseases; Metabolic stress; Modeling; Monitor; Mus; Myocardial; Myocarditis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Osmosis; Outcome; Oxidative Stress; Pathogenesis; Patients; Phenotype; Physiological; Process; Public Health; Published Comment; Pump; Quality of life; Receptor Protein-Tyrosine Kinases; Research; Resolution; Signal Pathway; Spleen; Suggestion; Surface; Testing; Therapeutic; Therapeutic Effect; Tissues; Treatment Failure; United States National Institutes of Health; Vascular Endothelial Cell; cell type; chronic inflammatory disease; comorbidity; coronary fibrosis; cytokine; db/db mouse; drug discovery; efficacy testing; fundamental research; heart function; improved; innovation; interest; molecular marker; monocyte; mortality; novel therapeutic intervention; preservation; prophylactic; receptor; reduce symptoms; response; single nucleus RNA-sequencing; subcutaneous; systemic inflammatory response

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（HF）治疗对于射血保留性心力衰竭无效 尽管美国所有 HF 病例中有 50% 是 HFpEF，但 HFpEF 患者的患病率却很高。 因此，迫切需要找到高死亡率、住院率和低生活质量的问题。 根据病理生理学，为 HFpEF 患者制定合适的治疗策略。 由于肥胖、糖尿病和高血压等全身合并症，病理生理学很复杂。 此类代谢疾病引起的炎症（又称代谢炎症）是驱动 HFpEF 的关键 慢性炎症是由于促炎症和消退之间的不平衡而发生的， 因此，我们计划开发合适的创新疗法来改善症状。 消退炎症以遏制 HFpEF 进展 消退是一个精心策划的过程。 专门的促分解介质 (SPM) 的作用，例如分解素、脂氧素和 maresins（分泌于 SPM 与其特定受体结合，通过进一步减少 白细胞浸润和胞吞增多，即清除心脏凋亡细胞。 有效的 SPM 之一，通过其受体甲酰肽受体 2 (FPR2) 发挥作用，并减少促炎、 促纤维化基因表达和细胞因子并促进胞吞作用，这些作用是通过极化介导的。 血液/骨髓来源的单核细胞和脾/心肌巨噬细胞从促炎到促- 然而，RVD1 在 HFpEF 中的作用是一个重大的临床问题。 尚未解决的炎症，尚未进行研究，我们的 R21 提案的主要目标是测试其功效。 RvD1 作为代谢性疾病驱动的 HFpEF 的潜在疗法因此，我们的建议符合 NIH 的目标。 特别兴趣 (NOSI-ES-20-018) 通知：促进炎症基础和应用研究 然而，在动物模型中模拟人类 HFpEF 的所有特征具有挑战性。 肥胖介导的 T2DM 模型，概括了 HFpEF 的主要特征，因此，我们选择采用 db/db； 我们的假设是，RvD1 通过小鼠来解决全身和心脏炎症。 重新编程单核细胞/巨噬细胞，从而改善与 HFpEF 相关的代谢应激。 提出两个具体目标来检验我们的假设：1）确定 RvD1 的预防作用；2） 确定 RvD1 的治疗效果 我们之前将用 RvD1 全身治疗小鼠（用于预防） 效果）和 HFpEF 发作后（治疗效果）我们将重点关注 RvD1 介导的 HFpEF 增加。 死亡心脏细胞的胞吞作用，即冠状血管内皮细胞（目标 1）和心肌细胞（目标 2） 作为其作用机制，该项目的预期结果是将 RvD1 作为一种治疗选择。 对于 HFpEF，一种没有合适治疗方法的慢性炎症性疾病，我们的创新理念旨在解决问题。 元炎症的研究可以推动 HFpEF 的药物发现研究向前发展。