赫赛汀是临床治疗多种HER2阳性实体瘤的一线药物，但高达13%的心脏毒性发生率限制了其长期安全使用，确切机制尚未阐明。我们前期发现赫赛汀引起的心脏毒性并不直接源于心肌细胞，而是通过血管内皮细胞引发心肌细胞收缩功能下降而产生的，其中血管内皮细胞释放的PTX3可能发挥了关键作用。进一步研究发现分泌型PTX3可能通过调控心肌细胞中钙调蛋白SMP30的降解而导致心肌细胞收缩功能下降。本课题将基于这一全新的发现，进一步明确血管内皮细胞在赫赛汀所致心脏毒性中的作用，确证PTX3释放在其中扮演的关键角色，阐明PTX3调控心肌细胞SMP30泛素蛋白酶体通路降解的分子过程，并探索SMP30泛素E3连接酶抑制剂作为干预赫赛汀心脏毒性策略的可行性。通过本课题的研究不仅可发现药源性心脏毒性发生的新模式，揭示PTX3调控心脏功能的新机制，提出SMP30蛋白稳定性调控的全新方式，还可为赫赛汀心脏毒性提供新的干预策略。

Herceptin, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), is approved as first-line treatment for solid tumors that over-expresses HER2 protein. Its use, however, has resulted in an unexpectedly high incidence (over 13%) of cardiotoxicity, which limits its safe use in clinic. The underlying mechanism is largely unknown. We previously found that the the cardiotoxicity of herceptin is through vascular endothelial cell-mediated myocardial cell contraction reduction, whereas is not directly relied on myocardial cell itself. And we also demonstrated that the secreted molecule, PTX3, specifically defined a key factor participate in vascular endothelial cell-mediated myocardial cell contraction reduction of herceptin. Furthermore, PTX3 promote myocardial cell contraction reduction through activating SMP30 degradation. Based on above results, we will first figure out the role of vascular endothelial cell in herceptin-induced cardiotoxicity. Next we will confirm the function of vascular endothelial cell-secrected PTX3 in this. What’s more, we will clarify the the molecular mechanism of PTX3-promoted SMP30 ubiquitin-proteasome degradation. In addition, we will confirm the feasibility of SMP30 E3 inhibitor to intervene the cardiotoxicity of herceptin. Taken together, our study will not only illustrate the novel model of drug-induced cardiotoxicity and determine the molecular mechanism of PTX3-mediated cardiac function, but also illuminate the innovate regulatory approach of the protein stability of SMP30 and explore potential intervention strategy for herceptin-induced cardiotoxicity.