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: 10540302
• 负责人: Mallory Filipp
• 金额: $ 4.19万
• 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/10540302
• 关键词: Affect; Anti-Inflammatory Agents; Apoptotic; Automobile Driving; Biopsy; Blood; Cardiac; Cardiac Myocytes; Categories; Cell Survival; Cells; Cellular Stress; Characteristics; Chronic; Clinic; Clinical; Collaborations; Data; Defect; Development; Diabetes Mellitus; Disease; E-Selectin; EFRAC; Echocardiography; Endothelial Cells; Endothelium; 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 Activation; Metabolic syndrome; Molecular; Mus; Myelogenous; 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; Symptoms; Syndrome; Testing; Tissues; Transforming Growth Factors; 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; macrophage; 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.

项目总结/摘要 射血分数保留性心力衰竭（HFpEF）是一种流行病，其发病率持续上升， 上升.尽管HFpEF的流行，经典的心力衰竭治疗和新的药物靶点未能 阐明一种有效的疗法。HFpEF的特征是心肌的“外部损伤”， 心脏合并症，如肥胖、高血压和代谢综合征。一种慢性的系统性低- 分级炎症诱导内皮细胞中活性氧（ROS）的产生和亚硝化应激。 这最终导致心肌细胞松弛受损，从而阻止左心室的适当充盈， 心脏储备 先天免疫系统是HFpEF背后的驱动力。由于全身炎症， 血管细胞粘附分子上调促进单核细胞迁移至内皮下 （VCAM）和E-选择素对内皮细胞的作用。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（TGF）-β。沿着观察到的心脏纤维化增加， 提示巨噬细胞（M β）活化的作用，然而，它们在HFpEF病理生理学中的确切功能 不明 在临床上，M β抗炎受体MerTK（solMER）的溶解形式的升高已经导致 探讨其在HFpEF中的作用。MerTK在维持组织稳态中起重要作用， 凋亡细胞的吞噬作用（吞噬作用）。然而，MerTK也在细胞存活、脂质摄取 和炎症消退。MerTK先前已通过以下方式参与缺血性损伤后的心脏修复： 促进垂死心肌细胞的吞噬作用。有趣的是，与缺血性损伤相反，我们的初步研究结果显示， 数据表明MerTK可能促进HFpEF而不是发挥其通常的心脏保护作用。 具体而言，该提案假设M β MerTK加剧了发展或 通过促进过度MerTK刺激的心脏纤维化引发HFpEF的持续性 高脂肪和亚硝化应激的HFpEF风险因素。该假设将通过以下方式进行检验： 与MerTK敲除和抑制组合的HFpEF小鼠模型。具体机制问题将 补充体外基因表达表征。拟议的研究将确定一个潜在的 治疗和预防HFpEF的新药物靶点，这是临床上迫切需要的。