期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 26, 期 20, 页码 5303-5314出版社
WILEY
DOI: 10.1111/jcmm.17560
关键词
ADAMTS13-TSP1 axis; apoptosis; CaMKII; cardiotoxicity; doxorubicin; endoplasmic reticulum stress; IRE1 alpha/XBP1s pathway
资金
- Foundation of Xi'an Municipal Bureau of Science and Technology [2019114613YX003SF036]
- National Natural Science Foundation of China [81774415, 82174493]
- Natural Science Basic Research Foundation for the Excellent Young of Shaanxi Province [S2018-JC-JQ-0094]
- Outstanding Youth Foundation of Shaanxi Province [2021JC-49]
This study found that CaMKII exacerbates Dox-induced cardiotoxicity by regulating the IRE1α/XBP1s pathway. Inhibition of CaMKII can improve cardiac dysfunction and pathological myocardial changes induced by Dox, preventing endoplasmic reticulum stress and apoptosis.
Doxorubicin (Dox), an anthracycline antibiotic with potent antitumor effects, has limited clinical applications due to cumulative cardiotoxicity. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is implicated in the pathological progression of Dox-induced cardiotoxicity. This study examined the hypothesis that CaMKII exacerbates Dox-induced cardiotoxicity by promoting endoplasmic reticulum stress and apoptosis through regulation of the inositol-requiring enzyme 1 alpha (IRE1 alpha)/spliced X-box binding protein 1 (XBP1s) pathway. Our results demonstrated that CaMKII activation and IRE1 alpha/XBP1s pathway were involved in Dox-treated hearts. CaMKII inhibition with KN-93 ameliorated Dox-induced cardiac dysfunction and pathological myocardial changes. In addition, CaMKII inhibition prevented Dox-induced endoplasmic reticulum stress and apoptosis. Moreover, CaMKII inhibition increased the expression of IRE1 alpha and XBP1s in Dox-treated hearts. The IRE1 alpha inhibitor 4 mu 8C blocked the protective effect of CaMKII inhibition against Dox-induced cardiotoxicity. Mechanistically, 4 mu 8C prevented the effects of CaMKII inhibition on Dox-induced endoplasmic reticulum stress and apoptosis by inhibiting the expression of IRE1 alpha and XBP1s. Additionally, treatment with rhADAMTS13 decreased the protein level of thrombospondin 1 (TSP1) and the phosphorylation of CaMKII in Dox-treated human AC16 cardiomyocytes. Taken together, these results demonstrate that the ADAMTS13-TSP1 axis regulates CaMKII activation and exacerbates Dox-induced cardiotoxicity by triggering endoplasmic reticulum stress and apoptosis by inhibiting the IRE1 alpha/XBP1s pathway.
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