MicroRNA let7-b and long non-coding RNAs in endothelial regeneration during atherosclerosis

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Atherosclerosis is a lipid-driven inflammatory disease that mainly develops at branching points of arteries and causes of myocardial infarction and stroke. Disturbed flow at these predilection sites induces endothelial cell (EC) dysfunction and limits endothelial regeneration upon hyperlipidemic stress by microRNA-mediated inhibition of Notch1 signaling. However, the molecular mechanisms regulating the regenerative capacity of arterial ECs are currently incompletely understood. Our preliminary results indicate that reduced expression of miRNA-let-7b in ECs protects against endothelial apoptosis, improves endothelial proliferation, and promotes Wnt and Notch1 signaling probably by targeting one or multiple long non-coding RNAs (lncRNAs). Therefore, I hypothesize that suppression of lncRNAs by let7b impairs regeneration of dysfunctional ECs during atherosclerosis by regulating the crosstalk of Wnt and Notch1 signaling pathways. To test this hypothesis, I will assess the effects of let-7b/lncRNA interactions on endothelial function and endothelial regeneration during atherosclerosis in mice and study whether these interactions impair endothelial regeneration and enhance atherosclerotic lesion formation by reduced activation of the Wnt/Notch axis. Moreover, I will investigate role of let-7b on regulating gene expression of Wnt and Notch1 pathway members in human ECs. I expect to identify a novel mechanism of endothelial regeneration during atherosclerosis characterized by the lncRNA induced activation of signaling pathways, such as Wnt and Notch, which are important for the arterial specification of ECs. Thus, targeting endothelial let-7b-lncRNA interactions may provide a new therapeutic strategy to improve endothelial health and decrease atherosclerosis.