Abstract
Doxorubicin (DOX) is a wide-spectrum antitumor drug, but its clinical application is limited by its cardiotoxicity. However, the mechanisms underlying DOX-induced cardiomyopathy remain mostly unclear. Here we observed that apoptosis repressor with caspase recruitment domain (ARC) was downregulated in mouse heart and cardiomyocytes upon DOX treatment. Furthermore, enforced expression of ARC attenuated DOX-induced cardiomyocyte mitochondrial fission and apoptosis. ARC transgenic mice demonstrated reduced cardiotoxicity upon DOX administration. DOX-induced mitochondrial fission required the activity of dynamin-related protein 1 (Drp1). In elucidating the molecular mechanism by which ARC was downregulated upon DOX treatment, miR-532-3p was found to directly target ARC and participated in DOX-induced mitochondrial fission and apoptosis. MiR-532-3p was not involved in DOX-induced apoptosis in cancer cells. Taken together, these findings provide novel evidence that miR-532-3p and ARC constitute an antiapoptotic pathway that regulates DOX cardiotoxicity. Therefore, the development of new therapeutic strategies based on ARC and miR-532-3p is promising for overcoming the cardiotoxicity of chemotherapy for cancer therapy.
Highlights
The heart has evolutionarily developed a highly expressed antiapoptotic protein, apoptosis repressor with caspase recruitment domain (ARC).[6]
Preservation of mitochondrial integrity is essential for maintaining energy production and preventing cell death
Various proteins participate in the regulation of mitochondrial dynamics
Summary
The heart has evolutionarily developed a highly expressed antiapoptotic protein, apoptosis repressor with caspase recruitment domain (ARC).[6] ARC was initially discovered as an endogenous apoptosis inhibitor in postmitotic cells, such as cardiomyocytes, skeletal muscle cells and neurons. It can antagonize both intrinsic and extrinsic apoptosis signaling pathways.[6,7,8] ARC has a role in maintaining physiological cardiac function. MiRNAs can regulate cardiac function such as the conductance of electrical signal, heart muscle contraction, heart growth and morphogenesis.[16] Manipulation of miRNA can be developed to therapeutic approaches It is not yet clear whether miRNAs are involved in the regulation of DOX cardiotoxicity. Our results identified a novel regulatory pathway for apoptosis involving miR-532-3p–ARC and possibly provide a valuable insight to protect against DOX cardiotoxicity during cancer chemical therapy
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