CD146/MCAM, initially identified as a cell surface receptor involved in cell proliferation and migration, has garnered significant attention for its potential contribution to the transcriptional process. In order to investigate the transcriptional regulation and function of CD146/MCAM in the heart, we employed doxorubicin, a widely used stressor for cardiomyocytes. Our in vitro study on H9c2 cardiomyoblasts highlights the activation of the transcriptional repressor Hes1, a downstream effector of the Notch signaling pathway, by doxorubicin. This activation results in decreased mRNA expression of fatty acid binding protein 4 (Fabp4), a crucial protein involved in lipid trafficking and metabolic responses. Furthermore, we found that silencing of CD146/MCAM leads to increased Fabp4 expression. Interestingly, the CD146/MCAM-driven upregulation of Fabp4 is sustained even in the presence of doxorubicin but is completely abolished upon inhibition of Notch signaling. These findings suggest that CD146/MCAM, in conjunction with Notch signaling, participates in the transcriptional regulation of Fabp4. Furthermore, we discovered that by acting as an upstream regulator of the histone deacetylases (HDACs), and bromodomain and extra-terminal domain proteins (BETs), protein kinase C (PKC) modulates the expression of CD146/MCAM. Moreover, inhibition of PKC suppresses nuclear CD146/MCAM and significantly reduces Fabp4 expression. In summary, our study unravels that CD146/MCAM acts as an intermediate molecule between Notch and PKC signaling in the doxorubicin-induced downregulation of Fabp4, and thereby might contribute to fatty acid transportation in cardiac cells.
*Correspondence: hasan@iwate-med.ac.jp; or, etaira@iwate-med.ac.jp