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激肽释放酶-PAR2-前炎症通路在严重曲妥珠单抗诱导的心脏毒性中的作用。

Involvement of kallikrein-PAR2-proinflammatory pathway in severe trastuzumab-induced cardiotoxicity.

机构信息

Department of Breast Oncology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

出版信息

Cancer Sci. 2022 Oct;113(10):3449-3462. doi: 10.1111/cas.15508. Epub 2022 Aug 19.

DOI:10.1111/cas.15508
PMID:35879248
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9530879/
Abstract

Trastuzumab-induced cardiotoxicity interferes with continued treatment in approximately 10% of patients with ErbB2-positive breast cancer, but its mechanism has not been fully elucidated. In this study, we recruited trastuzumab-treated patients with ≥30% reduction in left ventricular ejection fraction (SP) and noncardiotoxic patients (NP). From each of these patients, we established three cases of induced pluripotent stem cell-derived cardiomyocytes (pt-iPSC-CMs). Reduced contraction and relaxation velocities following trastuzumab treatment were more evident in SP pt-iPSC-CMs than NP pt-iPSC-CMs, indicating the cardiotoxicity phenotype could be replicated. Differences in ATP production, reactive oxygen species, and autophagy activity were observed between the two groups. Analysis of transcripts revealed enhanced kallikrein5 expression and pro-inflammatory signaling pathways, such as interleukin-1β, in SP pt-iPSC-CMs after trastuzumab treatment. The kallilkrein5-protease-activated receptor 2 (PAR2)-MAPK signaling pathway was more activated in SP pt-iPSC-CMs, and treatment with a PAR2-antagonist suppressed interleukin-1β expression. Our data indicate enhanced pro-inflammatory responses through kallikrein5-PAR2 signaling and vulnerability to external stresses appear to be the cause of trastuzumab-induced cardiotoxicity in SP.

摘要

曲妥珠单抗诱导的心脏毒性会干扰大约 10%的 ErbB2 阳性乳腺癌患者的持续治疗，但其机制尚未完全阐明。在这项研究中，我们招募了曲妥珠单抗治疗后左心室射血分数（SP）降低≥30%的患者和非心脏毒性患者（NP）。从每位患者中，我们建立了三种诱导多能干细胞衍生的心肌细胞（pt-iPSC-CMs）。与 NP pt-iPSC-CMs 相比，SP pt-iPSC-CMs 在曲妥珠单抗治疗后收缩和舒张速度降低更为明显，表明可以复制心脏毒性表型。两组之间观察到 ATP 产生、活性氧和自噬活性的差异。转录本分析显示，在曲妥珠单抗治疗后，SP pt-iPSC-CMs 中激肽释放酶 5 表达增强和促炎信号通路（如白细胞介素-1β）被激活。SP pt-iPSC-CMs 中的激肽释放酶 5-蛋白酶激活受体 2（PAR2）-MAPK 信号通路更活跃，用 PAR2 拮抗剂治疗可抑制白细胞介素-1β的表达。我们的数据表明，通过激肽释放酶 5-PAR2 信号增强的促炎反应和对外界应激的易感性似乎是 SP 中曲妥珠单抗诱导的心脏毒性的原因。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf19/9530879/c75b37832618/CAS-113-3449-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf19/9530879/154ad3be7bd2/CAS-113-3449-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf19/9530879/c75b37832618/CAS-113-3449-g008.jpg

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