期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 24, 期 18, 页码 10913-10923出版社
WILEY
DOI: 10.1111/jcmm.15719
关键词
apoptosis; autophagy; cardiotoxicity; doxorubicin; oxidative stress; TLR9
资金
- National Natural Science Foundation of China [81900219, 81530012, 81800216]
- Fundamental Research Funds for the Central Universities [2042019kf0062, 20142018kf1032]
- Development Center for Medical Science and Technology National Health and Family Planning Commission of the People's Republic of China [2016ZX-008-01]
- National Key R&D Program of China [2018YFC1311300]
Doxorubicin is a commonly used anthracycline chemotherapeutic drug. Its application for treatment has been impeded by its cardiotoxicity as it is detrimental and fatal. DNA damage, cardiac inflammation, oxidative stress and cell death are the critical links in DOX-induced myocardial injury. Previous studies found that TLR9-related signalling pathways are associated with the inflammatory response of cardiac myocytes, mitochondrial dysfunction and cardiomyocyte death, but it remains unclear whether TLR9 could influence DOX-induced heart injury. Our current data imply that DOX-induced cardiotoxicity is ameliorated by TLR9 deficiency both in vivo and in vitro, manifested as improved cardiac function and reduced cardiomyocyte apoptosis and oxidative stress. Furthermore, the deletion of TLR9 rescued DOX-induced abnormal autophagy flux in vivo and in vitro. However, the inhibition of autophagy by 3-MA abolished the protective effects of TLR9 deletion on DOX-induced cardiotoxicity. Moreover, TLR9 ablation suppressed the activation of p38 MAPK during DOX administration and may promote autophagy via the TLR9-p38 MAPK signalling pathway. Our study suggests that the deletion of TLR9 exhibits a protective effect on doxorubicin-induced cardiotoxicity by enhancing p38-dependent autophagy. This finding could be used as a basis for the development of a prospective therapy against DOX-induced cardiotoxicity.
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