MKP-1/TFEB轴调控自噬流在阿霉素心肌毒性中的作用及机制研究

阿霉素心肌毒性是肿瘤化疗病人最严重的并发症之一，可进一步发展为扩张型心衰甚至死亡，研究发生机制对防治有重要意义。丝裂原活化蛋白激酶磷酸酶-1（MKP-1）在心肌细胞表达，但在阿霉素引起心肌毒性中的作用尚不清楚。已报道：TFEB磷酸化使其不能移位入核，阻断溶酶体功能相关基因表达阻断自噬流，增加ROS产生和细胞死亡。我们研究发现：上调MKP-1能改善阿霉素引起的心肌细胞凋亡和心功能紊乱并下调TFEB磷酸化水平。据此，我们提出科学假说：MKP-1可能通过下调TFEB磷酸化，促进TFEB移位入核启动溶酶体功能相关基因表达，改善自噬流，减少ROS产生，降低心肌细胞死亡，从而改善阿霉素引起的心肌毒性。本研究拟利用原代心肌细胞和心肌细胞特异性过表达MKP-1转基因小鼠建立模型，探讨MKP-1在阿霉素心肌毒性发生中的作用及机制。本研究将以MKP-1为新视点揭示阿霉素心肌毒性的发生机制并为其防治提供新思路。

Doxorubicin-induced cardiotoxicity is one of the most serious complications in cancer patients undergoing chemotherapy. It could further develop into dilated heart failure or even death. Therefore, it is important to study the mechanism of doxorubicin induced cardiotoxicity for prevention and treatment. Mitogen-activated protein kinase phosphatase-1 (MKP-1) is expressed in cardiomyocytes, but its function in doxorubicin-induced cardiotoxicity remains unclear. Phosphorylation of TFEB prevents it from entering the nucleus, thereby blocking the expression of lysosome-related genes and autophagic flux, while doxorubicin blocking autophagic flux increases ROS production and cell death. We found that over-expression of MKP-1 improved doxorubicin-induced apoptosis in cardiomyocytes, and further study found that over-expression of MKP-1 decreased TFEB phosphorylation. Thus, we hypothesize that MKP-1 may reduce the doxorubicin-induced cardiotoxicity by downregulating TFEB phosphorylation thereby promoting its nuclear translocation to initiate lysosome-related genes expression, and improving autophagic flux, reducing ROS production and cell death in cardiomyocytes. The purpose of this study is to determine the mechanism of MKP-1 in doxorubicin-induced cardiotoxicity using primary cardiomyocyte model and MKP-1 myocardial cell-specific over-expression mice. This study will reveal the mechanism of doxorubicin-induced cardiotoxicity from a new perspective of MKP-1 and provide new ideas for the prevention and treatment of doxorubicin-induced cardiotoxicity.