Role of eosinophil cationic proteins in cardiac hypertrophy

嗜酸性粒细胞阳离子蛋白在心脏肥大中的作用

• 批准号: 10735136
• 负责人: Peter Libby
• 金额: $ 71.37万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-19 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735136
• 关键词: Adoptive Transfer; Adrenergic beta-Agonists; Agonist; Apoptosis; BMPR1A gene; Basic Science; Biological Markers; Blood; Bone Marrow; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cells; Clinical Research; Coronary heart disease; Cytoplasmic Granules; Diphtheria Toxin; Eosinophil cationic protein; Event; Female; Fibroblasts; Fibrosis; GATA1 gene; Growth Factor; Heart; Heart Block; Heart Hypertrophy; Heart failure; Human; Hypertension; Hypertrophy; IL4 gene; Inflammation; Infusion procedures; Injury; Isoproterenol; Left Ventricular Mass; Left ventricular structure; Lipids; MAPK8 gene; Maintenance; Measures; Molecular; Mus; PIK3CG gene; Pathogenesis; Pathway interactions; Patients; Phenotype; Prevalence; Proteins; Publishing; Reporting; Residual state; Risk; Risk Factors; Role; SARS-CoV-2 infection; Signal Transduction; Site; Testing; Thick; Transcriptional Regulation; Transforming Growth Factor beta; Ventricular; Ventricular septum; Work; aorta constriction; bone morphogenetic protein receptors; cardioprotection; cardiovascular disorder risk; chemokine; cytokine; eosinophil; gain of function; granule cell; human disease; indexing; loss of function; male; mortality; p38 Mitogen Activated Protein Kinase; pressure; prevent; protein expression; receptor; repaired; success

Coronary heart diseases remain the leading cause of deaths in the US. Despite the success of lipid lowering, residual risk remains. Current clinical studies support the participation of inflammation in cardiovascular diseases (CVD). Eosinophils (EOS) develop in the bone-marrow under the control of transcription factor GATA1. These granule cells accumulate in blood or at the site of inflammation. Blood EOS counts and EOS cationic protein (ECP) levels associate positively with the major CVD risk factors, prevalence, and mortality. Yet other studies reported reduced blood EOS counts and ECP levels in patients with major adverse cardiac events and heart failure (HF). Therefore, the role for EOS in human CVD remains unsettled. We reported that patients with hypertension showed positive association between blood EOS counts and hypertrophic measures. Using transverse aortic constriction (TAC)- and β-adrenergic receptor agonist isoproterenol (ISO)-induced cardiac hypertrophy and HF in EOS-deficient ∆dblGATA mice and in diphtheria toxin-induced EOS-depleted iPHIL mice, we demonstrated a reparative role of EOS in cardiac hypertrophy and HF by producing IL4 and cationic protein (mEar1). Mechanistic studies reported a role for EOS-derived IL4 and cationic proteins (mEar1, ECP) in blocking cardiomyocyte hypertrophy and apoptosis, and in inhibiting cardiac fibroblast TGF-β signaling and fibrosis. EOS granules contain cytokines, chemokines, growth factors, in addition to cationic proteins. To avoid ambitious concern, we will only study EOS cationic proteins in this proposal, as many other cells in hypertrophic heart also express these EOS cytokines, chemokines, and growth factors. Human EOS cationic protein ECP was identified 50 years ago and has been used as a biomarker for many human diseases, but it remains unknown whether and how ECP contributes to human diseases. Our preliminary studies showed that cardiomyocytes express bone morphogenetic protein receptor BMPR-1A and 1B, but not BMPR-2. In contrast, cardiac fibroblasts express BMPR-2 but not BMPR-1A or 1B. mEar1 uses BMPR-1A and 1B on cardiomyocytes as its receptor to activate the Smad-1/5/8 signaling and to block ISO-induced cardiomyocyte hypertrophy, but uses BMPR-2 on cardiac fibroblasts to block TGF-β-induced Smad2/3 signaling and fibrotic protein expression. In this proposal, we hypothesize that EOS protect heart from hypertrophy and HF by releasing cationic proteins to block cardiomyocyte hypertrophy and apoptosis and to inhibit cardiac fibroblast activation. EOS cationic proteins (mouse mEar1 and human ECP and EDN) exert their cardioprotective roles using BMPR-1A and 1B as their receptors on cardiomyocytes and BMPR-2 as their receptor on cardiac fibroblasts. Maintenance of functional receptors for EOS cationic proteins is essential to the cardioprotective role of human or mouse EOS. We propose two Aims to explore the molecular mechanisms by which EOS cationic proteins protect cardiomyocytes from hypertrophic injury and, to explore the molecular mechanisms by which EOS cationic proteins inhibit cardiac fibroblast fibrotic protein expression.

冠状动脉疾病仍然是美国死亡的主要原因。尽管降低脂质的成功， 残留风险仍然存在。当前的临床研究支持炎症参与心血管 疾病（CVD）。嗜酸性粒细胞（EOS）在转录因子控制下在骨row中发展 GATA1。这些颗粒细胞在血液或炎症部位积聚。血液EOS计数和EOS 阳离子蛋白（ECP）水平与主要的CVD风险因素，患病率和死亡率呈正相关。 然而其他研究报告说，主要不良心脏患者的血液EOS计数和ECP水平降低 事件与心力衰竭（HF）。因此，EOS在人类CVD中的作用仍未解决。我们报告了这一点 高血压患者在血液EOS计数与肥厚性测量之间显示正相关。 使用横向主动脉收缩（TAC）和β-肾上腺素受体激动剂异丙肾上腺素（ISO）诱导的 EOS缺乏ΔDBLGATA小鼠的心脏肥大和HF，以及白喉毒素诱导的EOS缺乏 iphil小鼠，我们通过产生IL4和 阳离子蛋白（MEAR1）。机械研究报道了EOS衍生的IL4和阳离子蛋白的作用（MeAR1， ECP）在阻断心肌细胞肥大和凋亡以及抑制心脏成纤维细胞TGF-β信号传导时 和纤维化。除阳离子蛋白外，EOS颗粒还含有细胞因子，趋化因子，生长因子。到 避免雄心勃勃的关注，我们只会在此提案中研究EOS阳离子蛋白，就像许多其他细胞 肥厚心脏还表达这些EOS细胞因子，趋化因子和生长因子。人EOS阳离子 蛋白质ECP被鉴定出50年前，已被用作许多人类疾病的生物标志物，但 ECP是否以及如何对人类疾病做出贡献仍然未知。我们的初步研究表明 心肌细胞表达骨形态发生蛋白受体BMPR-1A和1B，但不能表达BMPR-2。相比之下， 心脏成纤维细胞表达BMPR-2，但不表达BMPR-1A或1B。 MEAR1在 心肌细胞作为其受体，以激活SMAD-1/5/8信号并阻止ISO诱导的心肌细胞 肥大，但在心脏成纤维细胞上使用BMPR-2来阻止TGF-β诱导的SMAD2/3信号传导和纤维化 蛋白表达。在此提案中，我们假设EOS保护心脏免受肥大和HF的保护 释放阳离子蛋白以阻断心肌细胞肥大和凋亡，并抑制心脏成纤维细胞 激活。 EOS阳离子蛋白（小鼠MeAR1和人ECP和EDN）发挥其心脏保护作用 将BMPR-1A和1B作为心肌细胞上的受体，而BMPR-2作为心脏的受体 成纤维细胞。维持EOS阳离子蛋白的功能受体对于心脏保护是必不可少的 人或小鼠EOS的作用。我们提出了两个目的，以探索EOS的分子机制 阳离子蛋白保护心肌细胞免受肥厚性损伤，并通过 EOS阳离子蛋白抑制心脏成纤维细胞纤维化蛋白表达。