Hemin-driven chromatin remodelling by atherosclerotic risk geneSMARCA4switches human blood-derived macrophages from leukocyte disposal to erythrocyte disposal

Abstract

AbstractBackgroundPutative genetic risk loci for atherosclerotic vascular disease includeSMARCA4, a chromatin remodeling gene important for gene activation. Its causal role in atherosclerosis has been uncertain. Intraplaque hemorrhage (IPH) is a late event in atherosclerosis that is linked to plaque destabilisation and increased inflammation. IPH is countered by Mhem macrophages, which are directed by hemin-mediated induction of Heme Oxygenase 1 (HMOX1) via Activating Transcription Factor 1 (ATF1).Atf1deficiencyin vivoimpairs hematoma clearance, promoting inflammation and oxidative stress. Like its homologue cyclic-adenosine monophosphate response element binding protein 1 (CREB1), ATF1 is normally cyclic-AMP activated.HypothesisHemin-directed chromatin remodelling by SMARCA4 regulates specificity of ATF1 gene-binding, thereby switching between leukocyte disposal and erythrocyte disposal, contributing to its role in atherosclerosis.ResultsWe here show thatSMARCA4is genetically independent of the adjacentLDLRlocus (p<0.05). In human blood-derived macrophages, hemin triggered histone acetylation (H3K9Ac) and SMARCA4 recruitment in advance of p-ATF1 recruitment at theHMOX1enhancer. si-RNA-mediatedSMARCA4-knockdown suppressed p-ATF1 binding toHMOX1but increased its binding to cyclic-AMP responsive genesFOSandNR4A2, with corresponding changes in mRNA levels. This functionally correlated withSMARCA4-knockdown switching hemin to mimic prostacyclin (PGI2), for induced genes and phagocytic disposal of leukocytes rather than erythrocytes.ConclusionsThese data establishSMARCA4as an independent atherosclerosis risk gene and reveal a novel mechanism in which it switches between disposal of leukocytes or erythrocytes, with important clinical implications for atherosclerotic inflammation and intraplaque hemorrhage including treatment by histone deacetylase inhibitors.