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.

冠心病仍然是美国死亡的主要原因。尽管降脂取得了成功， 残余风险仍然存在。目前的临床研究支持炎症参与心血管疾病 疾病（CVD）。嗜酸性粒细胞 (EOS) 在转录因子的控制下在骨髓中发育 GATA1。这些颗粒细胞积聚在血液中或炎症部位。血液 EOS 计数和 EOS 阳离子蛋白 (ECP) 水平与主要 CVD 危险因素、患病率和死亡率呈正相关。 还有其他研究报告称，患有严重心脏不良事件的患者的血液 EOS 计数和 ECP 水平降低 事件和心力衰竭（HF）。因此，EOS 在人类 CVD 中的作用仍不确定。我们报道称 高血压患者的血 EOS 计数与肥厚指标呈正相关。 使用横主动脉缩窄 (TAC) 和 β-肾上腺素能受体激动剂异丙肾上腺素 (ISO) 诱导 EOS 缺陷 ΔdblGATA 小鼠和白喉毒素诱导的 EOS 耗尽的心脏肥大和心力衰竭 在 iPHIL 小鼠中，我们通过产生 IL4 和 IL4 证明了 EOS 在心脏肥大和心力衰竭中的修复作用 阳离子蛋白（mEar1）。机制研究报告了 EOS 衍生的 IL4 和阳离子蛋白（mEar1、 ECP）可阻断心肌细胞肥大和细胞凋亡，并抑制心脏成纤维细胞 TGF-β 信号传导 和纤维化。 EOS颗粒除阳离子蛋白外还含有细胞因子、趋化因子、生长因子。到 为了避免雄心勃勃的担忧，我们将在本提案中仅研究 EOS 阳离子蛋白，就像许多其他细胞一样 肥厚的心脏也表达这些EOS细胞因子、趋化因子和生长因子。人EOS阳离子 蛋白质 ECP 于 50 年前被鉴定出来，并已被用作许多人类疾病的生物标志物，但它 ECP 是否以及如何导致人类疾病仍不清楚。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 使用 BMPR-1A 和 1B 心肌细胞作为其受体激活 Smad-1/5/8 信号传导并阻断 ISO 诱导的心肌细胞 肥厚，但在心脏成纤维细胞上使用 BMPR-2 来阻断 TGF-β 诱导的 Smad2/3 信号传导和纤维化 蛋白质表达。在本提案中，我们假设 EOS 通过以下方式保护心脏免受肥大和心力衰竭： 释放阳离子蛋白，阻断心肌细胞肥大和凋亡，抑制心肌成纤维细胞 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 使用BMPR-1A和1B作为心肌细胞上的受体，BMPR-2作为心脏上的受体 成纤维细胞。维持 EOS 阳离子蛋白功能受体对于心脏保护至关重要 人类或小鼠 EOS 的作用。我们提出两个目标来探索 EOS 的分子机制 阳离子蛋白保护心肌细胞免受肥厚性损伤，并通过以下方式探索其分子机制 其中EOS阳离子蛋白抑制心脏成纤维细胞纤维化蛋白的表达。