MicroRNA-21 controls the circadian regulation of apoptosis in atherosclerotic lesions

Atherosclerosis is a leading cause of death due to the rupture of arterial lesions characterized by a necrotic core and inflammatory activity. Although lesion vulnerability follows a diurnal pattern with a higher incidence of rupture in the morning, the role of circadian rhythms in atherosclerotic lesions is unclear. Here we show that apoptosis in lesions follows a diurnal pattern that is controlled through the circadian regulation of the pro-apoptotic XIAP associated factor 1 (Xaf1) by the Mir21 strands. The increased apoptosis during the transition from the inactive to the active phase is not matched with the efferocytic removal of dead cells resulting in increased necrotic core formation. Lack of Mir21 expression in macrophages decreases atherosclerosis and necrotic core formation in mice, suggesting that Mir21-mediated diurnal apoptosis promotes lesion growth. In human atherosclerotic lesions, apoptosis also follows a diurnal pattern with a peak in the morning and oscillates in-phase with XAF1 expression and anti-phase with miR-21 expression. Thus, diurnal apoptosis regulated by a Mir21-controlled macrophage death clock may contribute to circadian regulation of lesion vulnerability. Gene expression in aortic arches was compared between BM Mir21–/– mice and BM Mir21+/+ mice after 12 weeks of an HFD feeding period by microarray analysis (n=3 mice per group).