Circadian rhythmicity of the thioredoxin system in cultured murine peritoneal macrophages

Macrophages play a pivotal role in atherosclerosis through a variety of events related to cellular oxidative stress. This process is mainly due to an excessive production of reactive oxygen species whose elimination occurs through antioxidant systems including the thioredoxin (Trx) system. In this paper, we investigated whether the Trx system would exhibit circadian rhythmicity in dexamethasone synchronized cultured macrophages and monitored the impact of the rhythmicity of Trx-1 on markers of atherosclerosis. We found that the clock-related genes BMAL-1, PER-2, CRY-1 and REV ERB α exhibited a robust circadian expression. However, the Trx genes family (Trx-1, Trx-2, TrxR1 and TXNIP) did not exhibit a circadian expression at the mRNA level in spite of the presence of E-box elements within the promoter regions of TrxR1 and TXNIP genes. Nevertheless, both Trx-1 and TXNIP exhibited a circadian expression at the protein level and proteasome inhibition abolished the rhythmicity of Trx-1. Moreover, we found a link between low Trx-1 level and elevated atherogenic markers such as 4-HNE, TNF-α and cholesterol accumulation in macrophages. Our results indicate that the Trx gene family does not exhibit the same circadian regulation and that the presence of E-box elements in the TXNIP promoter is not sufficient to ensure a circadian rhythmicity at the transcriptional level. In addition, since a link was found between a low level of Trx-1 protein during circadian rhythm and high levels of atherogenic markers, administration of Trx-1 at certain time points could be an interesting approach to protect against atherosclerosis development.