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Background  Increased macrophage and foam cell apoptosis during early atherogenesis retards plaque progression by impeding foam cell formation, suppressing inflammation and limiting lesion cellularity. Our previous in vitro study in THP1 macrophages demonstrated that  Terminalia Arjuna  (TA) attenuates dual-specificity phosphatase1 (DUSP1), a key negative regulator of JNK/P38MAPK signaling cascade, the branch also implicated in the UPR (unfolded protein response)-CHOP-mediated apoptotic pathway; however this pathway has not been explored so far in the presence of TA. Therefore, we aimed to elucidate the pro-apoptotic effect of aqueous bark extract of TA (aqTAE) on macrophage and foam cells and the underlying mechanism associated with it.    Methods  THP1 cells were initially differentiated into macrophages with phorbol-12-myristate-13-acetate (PMA) (100 ng/ml) for 24 h, followed by ox-LDL (100 μg/ml) treatment for another 24 h to induce foam cell formation. Thereafter, macrophages and ox-LDL- treated cells were incubated with aqTAE (100 μg/ml) for the next 24 h. Further, Oil Red O (ORO) staining, CD36 expression profiling, apoptotic assay and transcriptional and translational expression of ER-stress markers i.e., X-box binding protein 1 (XBP1) and C/EBP homologous protein (CHOP) were performed for elucidating the potential mechanism underlying TA-induced macrophage and foam cell apoptosis.    Results  We demonstrated that ox-LDL treatment significantly increased lipid accumulation and upregulated CD36 expression, indicating foam cell formation; while the addition of aqTAE resulted in a significant decline in ORO positive cells, and suppression of CD36 expression in ox-LDL-stimulated macrophages, suggestive of reduced formation of lipid-laden foam cells. Further, aqTAE treatment alone and in combination with oxidized low-density lipoprotein (ox-LDL) stimulus, significantly attenuated CD36 expression; increased apoptosis; and augmented the expression of UPR regulatory proteins including XBP1 and CHOP, and similar observations were noted when cells were treated with ox-LDL alone. These findings indicate that TA promotes macrophage and foam cell apoptosis via enhancing UPR-mediated activation of JNK/p38MAPK-CHOP pathway in a DUSP1-dependent manner, implying a possible interplay between ox-LDL-induced ER stress- and TA-mediated MAPK signaling.    Conclusion  Our data shows that aqTAE inhibits foam cell formation, as well as promotes macrophage and foam cell apoptosis by augmenting UPR- JNK/p38MAPK-CHOP signaling cascade via inhibiting DUSP1. These findings provide novel mechanistic insight into the anti-atherogenic potential of TA, which may prove beneficial against early-stage atherosclerotic lesions.

Terminalia Arjuna bark extract impedes foam cell formation and promotes apoptosis in ox-LDL-stimulated macrophages by enhancing UPR-CHOP pathway