Suppression of the neutrophil-derived S100A8/A9 complex ameliorates doxorubicin-induced cardiomyopathy in non-human primates.

Doxorubicin (DOX) is used for treatment of various cancers worldwide, but has a cumulative dose-dependent risk of irreversible cardiomyopathy. The mechanism of DOX-induced cardiomyopathy has not been fully elucidated because animal models such as rodents used in previous studies are largely different from humans in their physiological characteristics. In this study, we generated a DOX-induced cardiomyopathy model using non-human primates, cynomolgus monkeys, which are closely related to humans. After DOX was intravenously injected into the monkeys using the same protocol as that for humans, cardiac function was progressively impaired and fatal heart failure occurred, similar to those observed in patients who are treated with DOX. An RNA sequencing analysis identified S100A8 and S100A9 as genes that were the most highly expressed in the DOX-treated monkey heart, suggesting that gene products can exacerbate DOX-induced cardiomyopathy. Immunohistochemistry showed that neutrophils had abundantly infiltrated the DOX-treated monkey heart and were the major cell type that expressed the S100A8/A9 complex. After paquinimod (inhibitor of S100A8/A9) was administered to the monkeys together with DOX, cardiac function was preserved and cardiomyocyte damage was prevented. This administration suppressed the expression of proinflammatory cytokines and S100A8/A9-triggered adverse signaling pathways in the heart. Taken together, the DOX-induced cardiomyopathy model was successfully generated in the cynomolgus monkey. The S100A8/A9 complex may play a causal role in the onset and exacerbation of DOX-induced cardiomyopathy.