Kielin/chordin-like protein(KCP) deficiency exacerbates doxorubicin-induced myocardial injury by promoting macrophage M1 polarization through autophagy inhibition.

AIM: KCP has been demonstrated to be involved in cardiac remodeling and cardiac aging. This study aims to investigate whether KCP plays a regulatory role in doxorubicin (DOX)-induced cardiac injury by modulating immune and inflammatory responses.

RESULT: The expression of KCP in the left ventricle of a mouse model with doxorubicin-induced myocardial injury was detected using real-time quantitative PCR, Western blot, and immunofluorescence staining. The cardiac function of wild-type (WT) mice and KCP knockout (KO) mice was assessed via echocardiography, and histological analysis was further confirmed through immunofluorescence staining and HE staining. Bone marrow-derived macrophages (BMDM) were extracted from both wild-type (WT) mice and KCP knockout (KO) mice, and RNA sequencing was performed after doxorubicin treatment to identify differentially expressed genes and related signaling pathways. BMDM was utilized to validate the regulatory role and potential mechanisms of KCP in macrophage M1 polarization and the inflammatory response process. Studies have found that KCP expression is downregulated in the doxorubicin-induced myocardial injury model, and in vitro experiments revealed that doxorubicin treatment reduces KCP expression in BMDMs. KCP deficiency significantly exacerbates doxorubicin-induced cardiac dysfunction and myocardial injury, and promotes M1 polarization of macrophages. RNA sequencing results showed that KCP deficiency is associated with autophagy and the p38 MAPK signaling pathway after doxorubicin treatment. Further in vivo and in vitro studies suggest that KCP deficiency inhibits the autophagy process in BMDMs through the p38 MAPK/m-TOR pathway.

CONSLUSION: These results indicate that KCP deficiency exacerbates doxorubicin-induced myocardial injury in mice by promoting M1 polarization of BMDM through the p38 MAPK/m-TOR signaling pathway-mediated suppression of autophagy.