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.
Publisher
Cold Spring Harbor Laboratory