CD146/MCAM has garnered significant attention for its potential contribution to cardiovascular disease; however, the transcriptional regulation and functions remain unclear. To explore these processes regarding cardiomyopathy, we employed doxorubicin, a widely used stressor for cardiomyocytes. Our in vitro study on H9c2 cardiomyoblasts highlights that, besides impairing the fatty acid uptake in the cells, doxorubicin suppressed the expression of fatty acid binding protein 4 (Fabp4) along with the histone deacetylase 9 (Hdac9), bromodomain and extra-terminal domain proteins (BETs: Brd2 and Brd4), while augmented the production of CD146/MCAM. Silencing and chemical inhibition of Hdac9 further augmented CD146/MCAM and deteriorated fatty acid uptake. In contrast, chemical inhibition of BETs as well as silencing of MCAM/CD146 ameliorated fatty acid uptake. Moreover, protein kinase C (PKC) inhibition abrogated CD146/MCAM, particularly in the nucleus. Taken together, our results suggest that epigenetic dysregulation of Hdac9, Brd2, and Brd4 alters CD146/MCAM expression, deteriorating fatty acid uptake by downregulating Fabp4. This process depends on the PKC-mediated nuclear translocation of CD146. Thus, this study highlights a pivotal role of CD146/MCAM in doxorubicin-induced cardiomyopathy.
Keywords: BET inhibitor; Cardiotoxicity; Histone deacetylase; Protein kinase; Signal transduction.
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