Long non-coding RNA AK023617 orchestrates atherosclerosis by regulating the circadian rhythm of immunity-related GTPase family M protein in macrophages

Abstract

Acute coronary events show a diurnal rhythm, and atherosclerotic plaque vulnerability, as a histomorphological characteristic of major adverse cardiovascular events, is a key target for intervention. Although oscillating microRNAs reduce plaque stability by facilitating macrophage apoptosis in lesions, whether rhythmic long non-coding RNA (lncRNA) can regulate diurnal oscillations in plaque stability and the potential underlying mechanism remain unclear. In this study, we examined whether rhythmic lncRNAs are involved in the pathogenesis and progression of atherosclerosis and detected a novel circadian lncRNA-AK023617, which is positively correlated with the peak occurrence of major adverse cardiovascular events. Transfection of short interfering RNA specific to lnc-AK023617 into THP-1 cells dampened the oscillation of immunity-related GTPase family M protein 1 (Irgm1), which is negatively related to plaque stability. In ApoE^−/− mice fed a high-fat diet for 12 weeks, diurnal variations in lncAK023617 were consistent with the proportions of necroptotic cells in atherosclerotic plaques. In addition, reduced expression of lncAK023617 inhibited P-RIP3 and P-MLKL in THP-1 cells. Mechanistically, lncAK023617 interacted with the core molecular clock Bmal1 and promoted nuclear translocation of Bmal1, which could directly bind to the E-BOX elements in the Irgm1 promoter. Thus, oscillating lncAK023617 in macrophages can affect plaque stability by regulating necroptosis, which regulates circadian expression of the target gene Irgm1 by increasing the transcriptional activity of Bmal1, ultimately determining the diurnal oscillations in plaque stability. Therefore, lncAK023617 may serve as a specific target to ameliorate atherosclerotic plaque vulnerability.