多柔比星诱导的小鼠心血管毒性中收缩和舒张功能的特征,以及蛋白质组分析。

IF 3.2 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS
Dustin N Krüger, Matthias Bosman, Charles X L Van Assche, Callan D Wesley, Berta Cillero-Pastor, Leen Delrue, Ward Heggermont, Jozef Bartunek, Guido R Y De Meyer, Emeline M Van Craenenbroeck, Pieter-Jan Guns, Constantijn Franssen
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引用次数: 0

摘要

背景:蒽环类药物多柔比星(DOX蒽环类药物多柔比星(DOX)是一种高效抗癌药,尤其适用于乳腺癌和淋巴瘤。然而,DOX 可导致患者在治疗期间和幸存者出现癌症治疗相关心血管毒性(CTR-CVT)。目前,CTR-CVT 的诊断标准主要集中在左心室收缩功能障碍上,但需要达到一定的损伤程度才能发现。由于舒张功能障碍往往先于收缩功能障碍,本研究旨在确定 DOX 诱导的 CTR-CVT 的功能和分子标记物,重点关注舒张功能障碍:雄性 C57BL/6J 小鼠接受生理盐水或 DOX(4 毫克/千克,每周一次静脉注射)治疗 2 周和 6 周(累积剂量分别为 8 毫克/千克和 24 毫克/千克)(每个时间点每组 n = 8)。通过超声心动图和有创左心室压力测量对心血管功能进行纵向研究。随后,在两个时间点都获取心肌组织进行蛋白质组学研究(液相色谱-质谱联用技术)。一组 CTR-CVT 患者被用来补充临床前研究结果:结果:DOX诱导左心室射血分数在两周后从72±2%降至55±1%(累积8毫克/千克DOX)。舒张功能障碍表现为舒张时间延长(tau增加),6周后肺水肿(累积24毫克/千克DOX)明显导致心力衰竭。心肌蛋白质组分析显示,第6周时有12种蛋白质的表达量增加,其中SERPINA3N在DOX处理的动物中显著上调。人类同源蛋白 SERPINA3 曾被认为是 CTR-CVT 的标志物。小鼠心脏中 SERPINA3N 的上调通过 Western 印迹、免疫组化和 qPCR 得到了证实。因此,SERPINA3N 在血管内皮细胞中含量最高。在患者中,循环 SERPINA3 在 CTR-CVT 患者的血浆中增加,但在心脏活检中却没有增加:结论:我们发现小鼠在接受 DOX 治疗后会出现心力衰竭,收缩和舒张功能受损。此外,我们还在小鼠和 DOX 诱导的 CVT 患者体内发现了 SERPINA3 水平的升高,并证实了 SERPINA3 在心脏本身的表达,这表明 SERPINA3 可作为一种新型生物标记物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Characterization of systolic and diastolic function, alongside proteomic profiling, in doxorubicin-induced cardiovascular toxicity in mice.

Background: The anthracycline doxorubicin (DOX) is a highly effective anticancer agent, especially in breast cancer and lymphoma. However, DOX can cause cancer therapy-related cardiovascular toxicity (CTR-CVT) in patients during treatment and in survivors. Current diagnostic criteria for CTR-CVT focus mainly on left ventricular systolic dysfunction, but a certain level of damage is required before it can be detected. As diastolic dysfunction often precedes systolic dysfunction, the current study aimed to identify functional and molecular markers of DOX-induced CTR-CVT with a focus on diastolic dysfunction.

Methods: Male C57BL/6J mice were treated with saline or DOX (4 mg/kg, weekly i.p. injection) for 2 and 6 weeks (respectively cumulative dose of 8 and 24 mg/kg) (n = 8 per group at each time point). Cardiovascular function was longitudinally investigated using echocardiography and invasive left ventricular pressure measurements. Subsequently, at both timepoints, myocardial tissue was obtained for proteomics (liquid-chromatography with mass-spectrometry). A cohort of patients with CTR-CVT was used to complement the pre-clinical findings.

Results: DOX-induced a reduction in left ventricular ejection fraction from 72 ± 2% to 55 ± 1% after 2 weeks (cumulative 8 mg/kg DOX). Diastolic dysfunction was demonstrated as prolonged relaxation (increased tau) and heart failure was evident from pulmonary edema after 6 weeks (cumulative 24 mg/kg DOX). Myocardial proteomic analysis revealed an increased expression of 12 proteins at week 6, with notable upregulation of SERPINA3N in the DOX-treated animals. The human ortholog SERPINA3 has previously been suggested as a marker in CTR-CVT. Upregulation of SERPINA3N was confirmed by western blot, immunohistochemistry, and qPCR in murine hearts. Thereby, SERPINA3N was most abundant in the endothelial cells. In patients, circulating SERPINA3 was increased in plasma of CTR-CVT patients but not in cardiac biopsies.

Conclusion: We showed that mice develop heart failure with impaired systolic and diastolic function as result of DOX treatment. Additionally, we could identify increased SERPINA3 levels in the mice as well as patients with DOX-induced CVT and demonstrated expression of SERPINA3 in the heart itself, suggesting that SERPINA3 could serve as a novel biomarker.

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来源期刊
Cardio-oncology
Cardio-oncology Medicine-Cardiology and Cardiovascular Medicine
CiteScore
5.00
自引率
3.00%
发文量
17
审稿时长
7 weeks
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