Negative feedback regulation between microRNA let-7g and the oxLDL receptor LOX-1

Abstract

SummaryLectin-like oxidized LDL receptor-1 (LOX-1) is a surface scavenger receptor for oxidized low-density lipoprotein (oxLDL). Several transcription factors have been reported to regulate LOX-1 expression. MicroRNAs are small noncoding RNAs that control gene expression, but there have been no reports of LOX-1 expression being regulated by microRNAs. Because the microRNA let-7g has been predicted to bind to LOX-1 mRNA, we investigated whether let-7g can regulate LOX-1 expression. Our experiments first demonstrated that oxLDL can reduce let-7g expression. We later confirmed that there is a let-7g binding site on the 39-untranslated region of LOX-1 mRNA. We showed that intracellular Ca 2+ -activated protein kinase C is involved in the oxLDL-LOX-1-let-7g pathway. Bioinformatics predicted that the let-7g promoter has a binding site for the transcriptional repressor OCT-1. We used a promoter assay and chromatin immunoprecipitation to confirm this binding. Consequently, knockdown of OCT-1 was found to increase let-7g expression. Transfection of let-7g inhibited oxLDL-induced LOX-1 and OCT-1 expression, cell proliferation and migration. Mice fed with a high-fat diet showed a decrease in let-7g and an increase in LOX-1 and OCT-1. A study on humans showed the serum levels of let-7g are lower in subjects with hypercholesterolemia compared with normal controls. Our findings identify a negative feedback regulation between let-7g and LOX-1, and indicate that let-7g could be a target to treat cardiovascular disease.

Decreased MicroRNA-221 is Associated with High Levels of TNF-a in Human Adipose Tissue-Derived Mesenchymal Stem Cells From Obese Woman

“…miRNAs have been implicated in many biological processes, including cell proliferation [2], fat metabolism [2], differentiation [3], and cell death [3]. MicroRNAs have been shown to play a role in tumorigenesis [1], as well as several common diseases such as cardiovascular diseases [4,5] and diabetes [6,7]. Recent studies have also found that miRNAs play a regulatory role in adipogenic differentiation [8,9] and the development of obesity [10,11,12].…”

Circulating microRNAs predict future fatal myocardial infarction in healthy individuals – The HUNT study

“…Several studies have shown that let-7 family members have athero-protective effects. For instance, circulating levels of let-7i and let-7g-5p are decreased in patients with CHD and hypercholesterolemia, respectively [58,59]. Furthermore, decreased let-7g-5p levels have been shown to impair endothelial function and to increase the risks of CVD through targeting TGF-β signaling [60].…”

MicroRNA Let-7g and Atherosclerosis Plaque Stabilization

“…Frangogiannis et al reviewed the relation between let-7g and endothelial cell function and proposed that let-7g induced preservation on vascular diseases [17] [18]. Let-7g is indicated to negatively regulate lectin-like oxidized LDL receptor-1 (LOX-1) through the intracellular Ca 2+ -activated protein kinase C-oxLDL-LOX-1-let-7g pathway [19]. Furthermore, let-7g has been found as an important modulator in the development of atherosclerosis over the last 5 years [12] [17].…”