Let-7g suppresses both canonical and non-canonical NF-κB pathways in macrophages leading to anti-atherosclerosis.

Transformation of macrophages to foam cells contributes to atherosclerosis. Here, we report that let-7g reduces macrophage transformation and alleviates foam cell apoptosis by suppressing both canonical and non-canonical NF-κB pathways. In the canonical pathway, let-7g inhibits phosphorylation of IKKβ and IκB, down-regulates SREBF2 and miR-33a, and up-regulates ABCA1. In the non-canonical pathway, let-7g directly knocks down MEKK1, IKKα and ablates IKKα phosphorylation. Let-7g's effects in macrophages can be almost completely blocked by inactivation of NF-κB signaling, which suggests that let-7g's effects are primarily mediated through the suppression of NF-κB pathways. NF-κB has been reported to directly activate lin28 transcription, and lin28 is a well-known negative regulator for let-7 biogenesis. Therefore, there is negative feedback between NF-κB and let-7g. Additional macrophages-specific NF-κB knockout in the apoE deficiency mice reduces atherosclerotic lesion by 85%. Let-7g also suppresses p53-dependent apoptosis. Altogether, sufficient let-7g levels are important to prevent NF-κB over-activation in macrophages and to prevent atherosclerosis.