Cathepsin B Dependent Cleavage Product of Serum Amyloid A1 Identifies Patients with Chemotherapy-Related Cardiotoxicity.,ACS Pharmacology & Translational Science

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Cathepsin B Dependent Cleavage Product of Serum Amyloid A1 Identifies Patients with Chemotherapy-Related Cardiotoxicity.
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2019-09-03 , DOI: 10.1021/acsptsci.9b00035
Fangfang Zhang _{1,

2} , Christopher J Lyon ₂ , Robert J Walls ₂ , Bo Ning ₃ , Jia Fan ₂ , Tony Y Hu ₄

Affiliation

Improvements in long-term cancer survival rates have resulted in an increase in the prevalence of chemotherapy-linked cardiac failure, but treatment-induced cardiac injuries may not be detected until long after therapy. Monitoring cardiac function is recommended; however, cardiovascular injury in cancer patients differs from those with primary cardiac dysfunction, which limits the utility of traditional cardiac biomarkers. Here we examined plasma levels of peptides produced by cathepsin B, which is released during chemotherapy-induced cardiac injury. We applied nanotrap fractionation to enrich plasma peptides from cancer patients treated with or without chemotherapy. Peptides associated with chemotherapy-induced cardiotoxicity, but not other cardiac injury, were identified by mass spectrometry, and their dependence on cathepsin B activity was determined using enzyme inhibition experiments. We found that a peptide (SAA-1525) derived from serum amyloid A1 was significantly increased in cardiotoxicity patients, and its production was inhibited when plasma samples were pretreated with cathepsin B specific inhibitors. Plasma SAA-1525 also correlated with other markers of cardiac injury. Analysis of plasma SAA-1525 levels may hold potential as a rapid and minimally invasive method to monitor subclinical injury, thereby allowing timely intervention to mitigate further cardiac damage and avoid more severe clinical presentation.

中文翻译：

血清淀粉样蛋白A1的组织蛋白酶B依赖性裂解产物可确定与化疗有关的心脏毒性患者。

长期癌症生存率的提高已导致与化学疗法有关的心力衰竭的发生率增加，但是直到治疗后很长时间才可能发现由治疗引起的心脏损伤。建议监测心脏功能；但是，癌症患者的心血管损伤与原发性心脏功能障碍的患者不同，这限制了传统心脏生物标志物的实用性。在这里，我们检查了组织蛋白酶B产生的肽的血浆水平，该水平在化疗诱导的心脏损伤过程中释放。我们应用了纳米阱分级分离技术，以富集来自接受或未接受化学疗法治疗的癌症患者的血浆多肽。通过质谱法鉴定了与化学疗法诱发的心脏毒性有关的肽，但与其他心脏损伤无关的肽，并通过酶抑制实验确定它们对组织蛋白酶B活性的依赖性。我们发现，在心脏毒性患者中，源自血清淀粉样蛋白A1的肽（SAA-1525）显着增加，并且当血浆样品用组织蛋白酶B特异性抑制剂预处理时，其产生受到抑制。血浆SAA-1525也与心脏损伤的其他标志物相关。血浆SAA-1525水平的分析作为监测亚临床损伤的一种快速且微创的方法可能具有潜力，从而允许及时干预以减轻进一步的心脏损害并避免更严重的临床表现。当组织蛋白酶B特异性抑制剂预处理血浆样品时，其产生受到抑制。血浆SAA-1525也与心脏损伤的其他标志物相关。血浆SAA-1525水平的分析作为监测亚临床损伤的一种快速且微创的方法可能具有潜力，从而允许及时干预以减轻进一步的心脏损害并避免更严重的临床表现。当用组织蛋白酶B特异性抑制剂预处理血浆样品时，其产生受到抑制。血浆SAA-1525也与心脏损伤的其他标志物相关。血浆SAA-1525水平的分析作为监测亚临床损伤的一种快速且微创的方法可能具有潜力，从而允许及时干预以减轻进一步的心脏损害并避免更严重的临床表现。

更新日期：2019-09-04

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