J Leukoc Biol. 2026 Apr 29:qiag017. doi: 10.1093/jleuko/qiag017. Online ahead of print.
ABSTRACT
Macrophage dysfunction is hallmark of atherosclerotic disease, characterized by inflammation and uptake of oxidized low-density lipoproteins (oxLDL). We investigate the role of the epigenetic reader bromodomain-containing protein 4 (BRD4) in orchestrating macrophage responses through interactions with the mechanosensitive transcriptional coactivators YAP/TAZ. Suppression of BRD4 via bromodomain and extra-terminal motif (BET) protein inhibitors (BETi) unveils a remarkable capacity to mitigate YAP/TAZ-driven inflammation. Knockdown of YAP, TAZ or BRD4 in macrophages shows a significant convergence of inflammatory genes under the regulatory purview of these transcriptional regulators. In addition, persistent activation of YAP and TAZ initiates a partial inflammatory phenotype in macrophages, which is effectively ameliorated with BETi. Notably, CD36 and low-density lipoprotein (LDL) receptor-1 (LOX1), pivotal receptors involved in uptake of oxidized low-density lipoprotein (oxLDL), emerge as direct YAP/TAZ targets. We employed a BD2-specific BETi, ABBV-744, in an AAV-PCSK9-induced atherosclerosis model to test the therapeutic potential of BET inhibition. Although reduction in cholesterol levels is modest, BETi substantially curtails plaque formation, diminishing macrophage infiltration, and suppressing the upregulation of YAP/TAZ and oxLDL uptake receptors associated with atherogenesis. Intriguingly, even in conditions marked by heightened YAP/TAZ expression induced by myeloid cell-targeted YAP/TAZ overexpression, BETi effectively dampens inflammation, mitigates foam cell formation, and disease progression. Our work underscores the considerable promise of targeting the YAP/TAZ-BRD4 axis as a therapeutic strategy for averting atherosclerosis, thereby disrupting the relentless cycle of inflammation, mechanosensory responses, and oxLDL uptake characteristic of atherosclerosis progression.
PMID:42054500 | DOI:10.1093/jleuko/qiag017