Background
Chemotherapy-induced cardiovascular disease is a growing concern in the elderly population who have survived cancer, yet the underlying mechanism remains poorly understood. We investigated the role of ALKBH5 (AlkB homolog 5), a primary N6-methyladenosine (m6A) demethylase, and its involvement in m6A methylation-mediated regulation of targets in aging-associated doxorubicin-induced cardiotoxicity.
Conclusions
Our findings provide insights into the role of ALKBH5-m6A modification in modulating doxorubicin-induced cardiac dysfunction, remodeling, and cardiomyocyte apoptosis in male mice. These results highlight the potential of ALKBH5-targeted treatments for elderly patients with cancer in clinical settings.
Results
To validate the relationship between doxorubicin-induced cardiotoxicity and aging, we established young and old male mouse models. ALKBH5 expression was modulated through adeno-associated virus 9 (in vivo), Lentivirus, and siRNAs (in vitro) to examine its impact on cardiomyocyte m6A modification, doxorubicin-induced cardiac dysfunction, and remodeling. We performed mRNA sequencing, methylated RNA immunoprecipitation sequencing, and molecular assays to unravel the mechanism of ALKBH5-m6A modification in doxorubicin-induced cardiotoxicity. Our data revealed an age-dependent increase in doxorubicin-induced cardiac dysfunction, remodeling, and injury. ALKBH5 expression was elevated in aging mouse hearts, leading to reduced global m6A modification levels. Through mRNA sequencing and methylated RNA immunoprecipitation sequencing analyses, we identified ARID2 (AT-rich interaction domain 2) as the downstream effector of ALKBH5-m6A modulation in cardiomyocytes. Further investigations revealed that ARID2 modulates DNA damage response and enhances doxorubicin-induced cardiomyocyte apoptosis. Conclusions: Our findings provide insights into the role of ALKBH5-m6A modification in modulating doxorubicin-induced cardiac dysfunction, remodeling, and cardiomyocyte apoptosis in male mice. These results highlight the potential of ALKBH5-targeted treatments for elderly patients with cancer in clinical settings.