PTX3 from vascular endothelial cells contributes to trastuzumab-induced cardiac complications

作者：Zhifei Xu, Zizheng Gao, Huangxi Fu, Yan Zeng, Ying Jin, Bo Xu, Yuanteng Zhang, Zezheng Pan, Xueqin Chen, Xiaochen Zhang, Xiaohong Wang, Hao Yan, Xiaochun Yang, Bo Yang, Qiaojun He, Peihua Luo · 发表于：Cardiovascular Research · 年份：2023 · DOI：10.1093/cvr/cvad012 · 被引用次数：18 · 研究领域：Biomarkers in Disease Mechanisms、Cytokine Signaling Pathways and Interactions、HER2/EGFR in Cancer Research

AIMS: Trastuzumab, the first humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (ERBB2/HER2), is currently used as a first-line treatment for HER2 (+) tumours. However, trastuzumab increases the risk of cardiac complications without affecting myocardial structure, suggesting a distinct mechanism of cardiotoxicity. METHODS AND RESULTS: We used medium from trastuzumab-treated human umbilical vein endothelial cells (HUVECs) to treat CCC-HEH-2 cells, the human embryonic cardiac tissue-derived cell lines, and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to assess the crosstalk between vascular endothelial cells (VECs) and cardiomyocytes. Protein mass spectrometry analysis was used to identify the key factors from VECs that regulate the function of cardiomyocytes. We applied RNA-sequencing to clarify the mechanism, by which PTX3 causes cardiac dysfunction. We used an anti-human/rat HER2 (neu) monoclonal antibody to generate a rat model that was used to evaluate the effects of trastuzumab on cardiac structure and function and the rescue effects of lapatinib on trastuzumab-induced cardiac side effects. Medium from trastuzumab-treated HUVECs apparently impaired the contractility of CCC-HEH-2 cells and iPSC-CMs. PTX3 from VECs caused defective cardiomyocyte contractility and cardiac dysfunction in mice, phenocopying trastuzumab treatment. PTX3 affected calcium homoeostasis in cardiomyocytes, which led to defective contractile pr...