Hemopexin as an Early Biomarker of Anthracycline Cardiac Toxicity

项目摘要 该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。 蒽环类药物的心脏毒性通过利用人类患者和小鼠模型的研究。该项目将 由Beth Israel Deaconess Medical的心脏病学家兼肿瘤学主任Aarti Asnani博士领导 中心（BIDMC）和助理教授在哈佛医学院（HMS）。Asnani博士将与 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，如 多柔比星（Dox）是非常有效的化学疗法，但是它们的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不足， 因为它们不能反映毒性的潜在分子机制。为了满足这一未满足的需求，我们 使用基于适体的蛋白质组学测量了一组发现的女性中的1,300多种血浆蛋白质 用蒽环类药物治疗乳腺癌除了以前与细胞凋亡相关的蛋白质变化外， 蒽环类药物心肌病，我们确定了血红素结合蛋白（HPX）作为心脏毒性的新生物标志物，研究结果 其使用基于ELISA的测定在第二患者群组中验证。HPX是一种57 kDa的循环蛋白， 在肝脏中合成的糖蛋白，对含铁分子血红素具有高结合亲和力， 它是促氧化剂和炎性物质。在与血红素结合后，HPX经历受体介导的内吞作用， 通过LRP-1，其由循环巨噬细胞表达，并使血红素在脾脏中再循环 网状内皮系统这一血红素解毒途径主要由细胞内血红素介导 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HPX作为生物标志物的生物相容性， 此设置受这些人类发现的启发，我们使用了一个慢性阿霉素的小鼠模型， 心肌病，以评估HPX诱导蒽环类药物心脏毒性的机制影响。 基于我们的初步发现，我们假设HPX不仅是心脏毒性的生物标志物， 一种对蒽环类抗生素反应激活的心脏保护途径。我们将讨论这个假设， 本研究的目的如下：（1）研究HPX获得和功能丧失对心脏表型的影响， 慢性Dox心肌病小鼠模型;（2）通过以下方法确定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- 1调节;和（3）评估血液血红素，HPX和其他机制生物标志物的普遍性， 蒽环类药物治疗的不同患者人群的心脏毒性。除了建立HPX作为 作为蒽环类药物心脏毒性的生物标志物，这一研究路线将阐明血红素代谢在 心血管疾病更广泛。HPX和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.