PTX3 from vascular endothelial cells contributes to trastuzumab-induced cardiac complications.
PTX3 from vascular endothelial cells contributes to trastuzumab-induced cardiac complications.
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来自血管内皮细胞的 PTX3 导致曲妥珠单抗诱导的心脏并发症
DOI：
10.1093/cvr/cvad012
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发表时间：
2023-05-22
影响因子：
10.8
通讯作者：
中科院分区：
文献类型：
--
作者：
曲妥珠单抗是第一个针对人表皮生长因子受体2(ERBB2/HER2)的人源化单抗，目前被用作HER2(+)肿瘤的一线治疗药物。然而，曲妥珠单抗在不影响心肌结构的情况下增加了心脏并发症的风险，这表明心脏毒性的一个明显机制。我们使用曲妥珠单抗处理的人脐静脉内皮细胞(HUVECs)的培养液处理CCC-HEH-2细胞、人胚胎心脏组织来源的细胞系和人诱导的多能干细胞来源的心肌细胞(IPSC-CMS)，以评估血管内皮细胞(VECs)和心肌细胞之间的相互作用。用蛋白质质谱仪分析血管内皮细胞中调控心肌细胞功能的关键因子。我们应用RNA测序来阐明PTX3导致心功能障碍的机制。我们使用抗人/大鼠HER2(Neu)的单抗建立了一种大鼠模型，用于评价曲妥珠单抗对心脏结构和功能的影响以及拉帕替尼对曲妥珠单抗引起的心脏副作用的挽救作用。曲妥珠单抗处理的人脐静脉内皮细胞培养上清液对CCC-HEH-2细胞和IPSC-CMS的收缩能力有明显的损伤作用。来自血管内皮细胞的PTX3导致小鼠心肌细胞收缩功能缺陷和心功能障碍，表型复制曲妥珠单抗治疗。PTX3影响心肌细胞的钙稳态，从而导致收缩特性的缺陷。血管内皮细胞中的EGFR/STAT3信号通路促进了PTX3的表达和释放。值得注意的是，雷帕替尼是EGFR/HER2的双重抑制剂，可以通过阻断PTX3的释放来挽救曲妥珠单抗引起的心脏并发症。我们发现了一种独特的心脏毒性模式，其中曲妥珠单抗激活血管内皮细胞中的EGFR/STAT3信号促进PTX3的分泌，这通过抑制细胞钙信号而导致心肌细胞收缩能力受损。我们证实了拉帕替尼可能是一种可行的预防曲妥珠单抗引起的心脏并发症的药物，并为拉帕替尼和曲妥珠单抗联合应用于癌症治疗提供了理论基础。
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. 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 properties. EGFR/STAT3 signalling in VECs contributed to the increased expression and release of PTX3. Notably, lapatinib, a dual inhibitor of EGFR/HER2, could rescue the cardiac complications caused by trastuzumab by blocking the release of PTX3. We identified a distinct mode of cardiotoxicity, wherein the activation of EGFR/STAT3 signalling by trastuzumab in VECs promotes PTX3 excretion, which contributes to the impaired contractility of cardiomyocytes by inhibiting cellular calcium signalling. We confirmed that lapatinib could be a feasible preventive agent against trastuzumab-induced cardiac complications and provided the rationale for the combined application of lapatinib and trastuzumab in cancer therapy.
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影响因子：
29
作者：
Gorski PA;Ceholski DK;Hajjar RJ
通讯作者：
Hajjar RJ
影响因子：
5.4
作者：
McCormick ME;Collins C;Makarewich CA;Chen Z;Rojas M;Willis MS;Houser SR;Tzima E
通讯作者：
Tzima E
影响因子：
64.8
作者：
Litviňuková M;Talavera-López C;Maatz H;Reichart D;Worth CL;Lindberg EL;Kanda M;Polanski K;Heinig M;Lee M;Nadelmann ER;Roberts K;Tuck L;Fasouli ES;DeLaughter DM;McDonough B;Wakimoto H;Gorham JM;Samari S;Mahbubani KT;Saeb-Parsy K;Patone G;Boyle JJ;Zhang H;Zhang H;Viveiros A;Oudit GY;Bayraktar OA;Seidman JG;Seidman CE;Noseda M;Hubner N;Teichmann SA
通讯作者：
Teichmann SA
影响因子：
3.5
作者：
Ma H;Yin C;Zhang Y;Qian L;Liu J
通讯作者：
Liu J
影响因子：
37.8
作者：
Kitani, Tomoya;Ong, Sang-Ging;Wu, Joseph C.
通讯作者：
Wu, Joseph C.