Hemopexin as an Early Biomarker of Anthracycline Cardiac Toxicity

项目总结 本项目旨在为血红素代谢在糖尿病发病机制中的作用提供新的见解。 在人类患者和小鼠模型上进行的杠杆研究表明，蒽环类药物对心脏的毒性。该项目将是 由贝丝以色列女执事医疗中心心脏病专家兼心脏肿瘤科主任阿尔蒂·阿斯纳尼领导 他是哈佛大学医学院(HMS)助理教授。阿斯纳尼博士将与一家 多学科团队，将提供血红素和癌症生物学方面的专业知识。蒽环类药物 阿霉素(Dox)是一种非常有效的化疗药物，但其使用受到心脏毒性的限制。当前风险 在接受蒽环类药物治疗的患者中，分层和心脏保护策略是不够的，主要是 因为它们不能反映潜在的毒性分子机制。为了解决这一未得到满足的需求，我们 使用基于适体的蛋白质组学在一组发现的女性中测量了1300多种血浆蛋白质 用蒽环类药物治疗乳腺癌。除了先前与之相关的蛋白质的变化外 我们将血凝素(HPX)确定为心脏毒性的一个新的生物标志物。 这在第二个患者队列中使用基于ELISA的检测进行了验证。HPX是一个57 kDa的循环 在肝脏中合成的糖蛋白，与含铁分子血红素有很高的结合亲和力， 它是促氧化剂和炎症性物质。与血红素结合后，HPX经历受体介导的内吞作用 通过LRP-1，它由循环中的巨噬细胞表达，并使脾中的血红素循环 网状内皮系统。这种血红素解毒途径在很大程度上是由细胞内的血红素介导的 加氧酶-1。细胞内铁超载和巨噬细胞介导的炎症被描述为关键 DOX心脏毒性的分子机制，强调了HPX作为心脏毒性的生物标志物的生物学可行性 此设置。受这些人类发现的启发，我们使用了一种慢性阿霉素的小鼠模型 心肌病，以评估在蒽环类药物心脏毒性中诱导HPX的机制意义。 根据我们的初步发现，我们假设HPX不仅是心脏毒性的生物标记物，而且 一种心脏保护途径，对蒽环类药物有反应而被激活。我们将在 目的如下：(1)研究HPX的获得和丧失对急性心肌梗死患者心脏表型的影响。 慢性Dox心肌病小鼠模型；(2)明确HPX在Dox心脏毒性中的作用 HPX动力学和生物分布、血红素/铁代谢以及化学和遗传HO的综合分析 1调节；和(3)评估血色素、HPX和其他机械性生物标志物的概括性。 使用蒽环类药物治疗的不同患者群体的心脏毒性。除了将HPX建立为 ，这一系列研究将阐明血红素代谢在心脏毒性中的作用。 更广泛地说，心血管疾病。HPX及其相关通路的调节最终可能代表 在化疗期间保护心脏的新治疗策略。

PROJECT SUMMARY This project seeks to contribute new insights into the role of heme metabolism in the pathogenesis of anthracycline cardiac toxicity by leveraging studies in human patients and mouse models. The project will be led by Aarti Asnani, MD, Cardiologist and Director of Cardio-Oncology at Beth Israel Deaconess Medical Center (BIDMC) and Assistant Professor at Harvard Medical School (HMS). Dr. Asnani will collaborate with a multidisciplinary team that will provide expertise in heme and cancer biology. Anthracyclines such as doxorubicin (Dox) are very effective chemotherapies, but their use is limited by cardiac toxicity. Current risk stratification and cardioprotective strategies are inadequate in patients treated with anthracyclines, largely because they do not reflect the underlying molecular mechanisms of toxicity. To address this unmet need, we used aptamer-based proteomics to measure over 1,300 plasma proteins in a discovery cohort of women treated with anthracyclines for breast cancer. In addition to changes in proteins previously associated with anthracycline cardiomyopathy, we identified hemopexin (HPX) as a new biomarker of cardiac toxicity, findings that were validated in a second patient cohort using an ELISA-based assay. HPX is a 57-kDa circulating glycoprotein synthesized in the liver that has a high binding affinity for the iron-containing molecule heme, which is pro-oxidant and inflammatory. Upon binding to heme, HPX undergoes receptor-mediated endocytosis via LRP-1, which is expressed by circulating macrophages and enables heme recycling in the splenic reticuloendothelial system. This heme detoxification pathway is largely mediated by intracellular heme oxygenase-1. Intracellular iron overload and macrophage-mediated inflammation have been described as key molecular mechanisms of Dox cardiac toxicity, underscoring the biological plausibility of HPX as a biomarker in this setting. Motivated by these human findings, we used a mouse model of chronic doxorubicin cardiomyopathy to assess the mechanistic implications of HPX induction in anthracycline cardiac toxicity. Based on our preliminary findings, we hypothesize that HPX is not only a biomarker of cardiac toxicity, but also a cardioprotective pathway that is activated in response to anthracyclines. We will address this hypothesis in the following aims: (1) To characterize the effects of HPX gain and loss-of-function on cardiac phenotypes in a mouse model of chronic Dox cardiomyopathy; (2) To define the role of HPX in Dox cardiac toxicity through integrative analyses of HPX kinetics and biodistribution, heme/iron metabolism, and chemical and genetic HO- 1 modulation; and (3) To assess the generalizability of blood heme, HPX, and other mechanistic biomarkers of cardiac toxicity in diverse patient populations treated with anthracyclines. In addition to establishing HPX as a biomarker of anthracycline cardiac toxicity, this line of investigation will clarify the role of heme metabolism in cardiovascular disease more broadly. Modulation of HPX and associated pathways could ultimately represent a new therapeutic strategy to protect the heart during chemotherapy.