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

Abstract

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.

Circulating small non-coding RNAs provide new insights into vitamin K nutrition and reproductive physiology in teleost fish

“…An inflammatory response suppression has been found to be mediated by miR-146a [94] and higher expression of miR-146a was associated with atherosclerotic arteries [95]. Also, let-7g has been reported to prevent atherosclerosis [96], while let-7e is known as an important regulator of endothelial function and inflammation, and might be a key molecule on the development of atherosclerosis [97].…”

Indoxyl Sulfate Promotes Macrophage IL-1β Production by Activating Aryl Hydrocarbon Receptor/NF-κ/MAPK Cascades, but the NLRP3 inflammasome Was Not Activated

“…For example, in vitro, LPS enhances the phosphorylation of mouse macrophage NF-κ p65, Ik-, ERK, JNK, and p38, which was inhibited by SC-E3, a novel herbal formula [ 25 ]. Macrophage-specific NF-κB knockout in apolipoprotein E-deficient mice reduced the high-fat-diet-induced acceleration of atherosclerosis [ 26 ]. In contrast, IS activated NF-κB/MAPK cascades, which enhanced inflammatory reactions in several cell types.…”

MicroRNA sequences modulating inflammation and lipid accumulation in macrophage “foam” cells: Implications for atherosclerosis

“…Over the last five years, there has been an explosion of interest in the role of miRNA involved in macrophage biology, and in “foam” cell formation in particular. Table 1 [ 153 , 155 - 204 ] indicates some of the miRNA sequences identified by interrogation of the NCBI PubMed database, as either altered by uptake of modified LDL by macrophages, or implicated in the pathogenesis of foam cell formation. Many of the genes targeted by these sequences play established roles in either lipid metabolism or inflammation, but a significant number have no prior links to either process, highlighting the importance of miRNA research in driving the discovery of novel cellular processes contributing to disease.…”

“…miRNA sequences which target the expression of proteins within cell signalling pathways mediating inflammatory responses have also been shown to reduce cholesterol accumulation in macrophages (Table 1 )[ 153 , 155 - 204 ]. For instance, let-7g inhibits both canonical (RelA/p50) and non-canonical (RelB/p52) NF-κB signalling pathways, limiting inflammatory (IL-1, IL-6, MCP-1) and apoptotic responses, and decreasing macrophage foam cell formation[ 155 ] in vitro and in vivo . Further, let-7g inhibition of nuclear translocation of RelA/p50 in macrophages treated with OxLDL prevents NF-κB dependent upregulation of SREBF2 and miR-33a, and results in up-regulation of ABCA1[ 155 ].…”

“…For instance, let-7g inhibits both canonical (RelA/p50) and non-canonical (RelB/p52) NF-κB signalling pathways, limiting inflammatory (IL-1, IL-6, MCP-1) and apoptotic responses, and decreasing macrophage foam cell formation[ 155 ] in vitro and in vivo . Further, let-7g inhibition of nuclear translocation of RelA/p50 in macrophages treated with OxLDL prevents NF-κB dependent upregulation of SREBF2 and miR-33a, and results in up-regulation of ABCA1[ 155 ]. Indeed, aberrant expression of members of the lethal-7 (let-7) miRNA family have been linked with a number of diseases, including atherosclerosis and cancer[ 205 - 207 ]: Reductions in expression of let-7, which can be mediated by RNA binding protein Lin-28 homolog A (Lin-28), is observed in human carotid plaques from diabetic individuals, and diabetic apoE -/- mice[ 207 ].…”