MerTK as a new target to understand and ameliorate HFpEF

MerTK 作为理解和改善 HFpEF 的新目标

• 批准号: 10591556
• 负责人: Mallory Filipp
• 金额: $ 4.3万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591556
• 关键词: Affect; Anti-Inflammatory Agents; Apoptotic; Automobile Driving; Biopsy; Blood; Cardiac; Cardiac Myocytes; Cell Survival; Cells; Cellular Stress; Characteristics; Chronic; Classification; Clinic; Clinical; Collaborations; Data; Defect; Development; Diabetes Mellitus; Disease; E-Selectin; EFRAC; Echocardiography; Endothelial Cells; Engineering; Epidemic; Failure; Family; Fatigue; Fatty acid glycerol esters; Fibrosis; Functional disorder; Gene Expression; Generations; Genetic Transcription; Heart; Heart failure; Homeostasis; Hypertension; Impairment; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Innate Immune System; Knock-out; Left; Left ventricular structure; Leukocytes; Lipids; Liquid substance; Macrophage; Macrophage Activation; Metabolic syndrome; Molecular; Mus; Myelogenous; Myocardial dysfunction; Myocardium; Nitric Oxide; Obesity; Pathway interactions; Patients; Peptide Hydrolases; Phagocytosis; Phase; Plasma; Play; Prevalence; Prevention; Production; Proteins; Reactive Oxygen Species; Relaxation; Resistance; Resolution; Risk Factors; Role; Secondary to; Serum; Signal Pathway; Signal Transduction; Stress; Subcategory; Symptoms; Syndrome; Testing; Tissues; Transforming Growth Factor beta; Treatment Failure; Up-Regulation; Validation; Vascular Cell Adhesion Molecule-1; Ventricular; Ventricular Remodeling; arm; cardiac repair; cardioprotection; chronic inflammatory disease; comorbidity; coronary fibrosis; cytokine; driving force; effective therapy; exercise intolerance; in vivo; ineffective therapies; insight; ischemic injury; migration; monocyte; mortality; mouse model; new therapeutic target; nitrosative stress; preservation; prevent; profibrotic cytokine; receptor; response; single-cell RNA sequencing; small molecule inhibitor; systemic inflammatory response; targeted treatment; therapeutic evaluation; therapeutic target; transcriptional reprogramming; uptake

Project Summary/Abstract Heart failure with preserved ejection fraction (HFpEF) is an epidemic and the incidence is continuing to rise. Despite the prevalence of HFpEF, classical heart failure treatments and novel drug targets have failed to elucidate an effective therapy. HFpEF is characterized by “damage from without” the myocardium with extra- cardiac comorbidities such as obesity, hypertension and metabolic syndrome. A chronic state of systemic low- grade inflammation induces reactive oxygen species (ROS) production in endothelial cells and nitrosative stress. This culminates in impaired cardiomyocyte relaxation preventing proper filling of the left ventricle and reduced cardiac reserve. The innate immune system is a driving force behind HFpEF. As a result of systemic inflammation, monocyte migration into the sub-endothelium is promoted by upregulations in vascular cell adhesion molecule (VCAM) and E-selectin on endothelial cells. Additionally, cardiac biopsies of HFpEF patients show elevations in the pro-fibrotic cytokine transforming growth factor (TGF)-β. Along with observed increased cardiac fibrosis, this suggests a role for the activation of macrophages (Mɸ), however, their exact function in HFpEF pathophysiology is unknown. Clinically, elevations in the solubilized form of Mɸ anti-inflammatory receptor MerTK (solMER) have led us to explore its function in HFpEF. MerTK plays an important role in maintaining tissue homeostasis through phagocytosis of apoptotic cells (efferocytosis). However, MerTK also plays a role in cell survival, lipid uptake, and inflammation resolution. MerTK has previously been implicated in cardiac repair after ischemic injury by promoting phagocytosis of dying cardiomyocytes. Interestingly, in contrast to ischemic injury, our preliminary data suggest that MerTK may be promoting HFpEF instead of acting in its usual cardioprotective role. Specifically, this proposal hypothesizes that Mɸ MerTK exacerbates the development or persistence of HFpEF through the promotion of excessive MerTK-stimulated cardiac fibrosis triggered by the combined HFpEF risk factors of high fat and nitrosative stress. This hypothesis will be tested using mouse models of HFpEF in combination with MerTK knockout and inhibition. Mechanism-specific questions will be supplemented with in vitro gene expression characterization. The proposed studies will identify a potential new drug target for treatment and prevention of HFpEF, something desperately needed in clinic.

项目摘要/摘要 射血分数保留的心力衰竭(HFpEF)是一种流行病，其发病率仍在继续 站起来。尽管HFpEF盛行，但传统的心力衰竭治疗和新的药物靶点未能奏效 阐明一种有效的治疗方法。HFpEF的特点是“来自外部”的心肌损伤和额外的- 心脏合并症，如肥胖、高血压和代谢综合征。一种全身性低血压的慢性状态 分级炎症可诱导内皮细胞产生活性氧(ROS)和亚硝化应激。 这最终导致心肌细胞松弛受损，阻碍了左心室的正常充盈，并减少了 心脏储备。 先天免疫系统是HFpEF背后的驱动力。作为全身炎症的结果， 血管细胞黏附分子上调促进单核细胞向内皮下层迁移 血管内皮细胞黏附分子(VCAM)和E-选择素。此外，HFpEF患者的心脏活检显示 促纤维化细胞因子转化生长因子-β。随着观察到的心脏纤维化的增加，这 提示巨噬细胞(Mɸ)的激活作用，然而，它们在HFpEF病理生理学中的确切功能 是未知的。 临床上，M-ɸ抗炎受体MerTK(Solmer)溶解形式的升高导致 以探讨其在HFpEF中的作用。MerTK在维持组织动态平衡中发挥重要作用 凋亡细胞的吞噬作用(胞泡吞噬)。然而，MerTK也在细胞存活、脂质摄取、 和消炎作用。MerTK此前被认为与心脏缺血损伤后的修复有关，通过 促进死亡心肌细胞的吞噬功能。有趣的是，与缺血性损伤相比，我们的初步研究 数据表明，MerTK可能是在促进HFpEF，而不是发挥其通常的心脏保护作用。 具体地说，这一提议假设Mɸmertk加剧了发展或 HFpEF通过促进MerTK过度刺激引发的心肌纤维化而持续 由高脂和亚硝酸盐应激合并的HFpEF危险因素所致。这一假设将通过以下方式进行检验 HFpEF结合MerTK基因敲除和抑制的小鼠模型。机制特定的问题将 补充体外基因表达特征。拟议的研究将确定潜在的 治疗和预防HFpEF的新药物靶点，这是临床迫切需要的。