Conclusion
The study reports for the first time chronodisruption mediated miR34a-5p elevation, its circadian expression and interaction with the 3'UTR of Clock gene to impede its expression. Moreover, elevated miR34a-5p and lowered SIRT1 expression in the chronodisruptive aortae lead off cause-consequence relationship of chronodisruption mediated proatherogenic changes.
Results
Chronodisruption induced hypomethylation in the promoter region of miR34a-5p, in the thoracic aortae, culminating in elevated miRNA titers. In a software-based detection of circadian-clock-associated targets of miR34a-5p, Clock and Sirt1 genes were identified. Moreover, miR34a-5p exhibited antagonist circadian oscillations to that of its target genes CLOCK and SIRT1 in endothelial cells. Luciferase reporter gene assay further showed that miR34a-5p interacts with the 3'UTR of the Clock gene to lower its expression, disturbing the operation of positive arm of circadian clock system. Elevated miR34a-5p and impeded SIRT1 expression in a chronodisruptive aortae exhibited pro-atherogenic changes observed in form of gene expression, increased collagen/elastin ratio, fibrillar derangement and intimal-media thickening.