CaMKII Exacerbates Doxorubicin‐Induced Cardiotoxicity by Promoting Ubiquitination Through USP10 Inhibition.

Background: Doxorubicin (DOX) is an effective anticancer drug, but it has a problem of cardiotoxicity that cannot be ignored. Ca2+/calmodulin‐dependent protein kinase II (CaMKII) is tightly associated with the pathological progression of DOX‐induced cardiotoxicity. Ubiquitin‐specific protease 10 (USP10) plays an important role in many biological processes and cancers. However, its association with DOX‐induced cardiotoxicity and CaMKII remains unclear. Methods: H9C2 cells, HL‐1 cells and C57BL/6 mice were used to establish the DOX‐induced cardiotoxicity model, and the CaMKII‐specific inhibitor KN‐93 and USP10 specific inhibitor Spautin‐1 were used to observe the CaMKII and USP10 effect. In cell experiments, CCK‐8 method was used to assess cell viability, LDH kit was used to assess lactate dehydrogenase expression, DCFH‐DA staining was used to observe changes in active oxygen content, TUNEL staining was used to observe cell apoptosis, and Western blotting method was used to detect relevant protein markers. The expression of p‐CaMKII and USP10 was assessed by immunofluorescence staining. In animal experiments, mouse echocardiograph was used were used to evaluate cardiac function, and HE staining and Masson staining were used to evaluate myocardial injury. Cardiomyocyte apoptosis was detected by TUNEL staining. Western blotting method was used to detect relevant protein markers. Results: Our results demonstrated that activation of CaMKII and inhibition of USP10 pathway related to DOX‐induced cardiotoxicity. Inhibition of CaMKII with KN‐93 ameliorated DOX‐induced cardiac dysfunction and cytotoxicity. In addition, CaMKII inhibition prevented DOX‐induced apoptosis and ubiquitination. Furthermore, CaMKII inhibition increased USP10 expression in DOX‐treated mouse hearts, H9C2 cells and HL‐1 cells. At last, the USP10 inhibitor, Spautin‐1, blocked the regulatory effect of CaMKII inhibition on apoptosis and ubiquitination in DOX‐induced cardiotoxicity. Conclusion: Our findings revealed that DOX‐induced myocardial apoptosis and activated CaMKII through cellular and animal levels, while providing a novel probe into the mechanism of CaMKII action: promoting ubiquitination by inhibiting USP10 aggravated apoptosis. [ABSTRACT FROM AUTHOR]