Cardiomyocyte-specific knockout of ADAM17 alleviates doxorubicin-induced cardiomyopathy via inhibiting TNFa-TRAF3-TAK1-MAPK axis

Doxorubicin as a commonly used anthracycline has become the cornerstone of chemotherapy in a wide range of cancers owing to its high efficacy. However, clinical applications of doxorubicin are limited mainly due to its toxic effects on myocardium but the pathogenic mechanism of doxorubicin-induced cardiomyopathy are poorly understood. ADAM17 is known as tumor necrosis factor a converting enzyme (TACE), and the cleavage of TNF-a by ADAM17 is a prerequisite for pro-inflammatory TNF-a activity, which raises a possibility that inhibition of ADAM17 may exert a beneficial effect on disease processes where TNF-a plays an essential role. Our previous research has shown that cardiomyocyte specific knockout of ADAM17 improves diabetic cardiomyopathy by modulating cardiomyocyte apoptosis. However, the relationship between ADAM17 and doxorubicin-induced cardiomyopathy is unclear.Through RNA sequencing analysis, we observed significant changes in the TNF signaling pathway genes in the heart tissue of mice with or without cardiomyocyte ADAM17 knockout. Overall design: The gene expression of 3 samples from ADAM17flox/flox+NS was compared to 3 samples from ADAM17flox/flox+DOX by RNA-sequencing. And the gene expression of 3 samples from ADAM17flox/flox+DOX was compared to 3 samples from ADAM17a-MHCKO+DOX were compared by RNA sequencing.