Role of eosinophil cationic proteins in cardiac hypertrophy

冠心病仍然是美国人死亡的主要原因。尽管降脂治疗取得了成功， 剩余风险依然存在。目前的临床研究支持炎症在心血管疾病中的作用。 疾病（CVD）。嗜酸性粒细胞（EOS）在转录因子的调控下在骨髓中发育 GATA 1.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。 然而，其他研究报告了严重不良心脏事件患者的血液EOS计数和ECP水平降低。 事件和心力衰竭（HF）。因此，EOS在人类CVD中的作用仍然不确定。我们报道了 高血压患者血EOS计数与肥厚指标呈正相关。 使用横主动脉收缩（TAC）和β-肾上腺素能受体激动剂异丙肾上腺素（ISO）诱导 EOS-缺陷的EodblGATA小鼠和白喉毒素诱导的EOS-缺失的EodblGATA小鼠中的心脏肥大和HF 在iPHIL小鼠中，我们证明了EOS通过产生IL 4和IL-6在心肌肥厚和HF中的修复作用。 阳离子蛋白（mEar1）。机制研究报道了EOS衍生的IL 4和阳离子蛋白的作用（mEar1， ECP）阻断心肌细胞肥大和凋亡，并抑制心脏成纤维细胞TGF-β信号传导 和纤维化。EOS颗粒含有细胞因子、趋化因子、生长因子以及阳离子蛋白。到 避免雄心勃勃的关注，我们将只研究EOS阳离子蛋白在这个建议，因为许多其他细胞在 肥大心脏也表达这些EOS细胞因子、趋化因子和生长因子。人EOS阳离子 蛋白ECP在50年前被发现，并已被用作许多人类疾病的生物标志物，但它 目前还不清楚ECP是否以及如何导致人类疾病。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。与此相反， 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信号并阻断ISO诱导的心肌细胞 肥大，但使用心脏成纤维细胞上的BMPR-2来阻断TGF-β诱导的Smad2/3信号传导和纤维化。 蛋白质表达在这个提议中，我们假设EOS通过以下方式保护心脏免受肥大和HF的影响： 释放阳离子蛋白，阻断心肌细胞肥大和凋亡，抑制心脏成纤维细胞 activation. EOS阳离子蛋白（小鼠mEar1和人ECP和EDN）发挥其心脏保护作用 用BMPR-1A和1B作为它们在心肌细胞上的受体，BMPR-2作为它们在心肌细胞上的受体， 成纤维细胞EOS阳离子蛋白功能性受体的维持对于心肌保护是必要的。 人或小鼠EOS的作用。我们提出了两个目的来探讨EOS的分子机制， 阳离子蛋白保护心肌细胞免受肥厚性损伤， 所述EOS阳离子蛋白抑制心脏成纤维细胞纤维化蛋白表达。

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.