Peroxisome Proliferator-Activated Receptor- γ Antagonizes LOX-1-Mediated Endothelial Injury by Transcriptional Activation of miR-590-5p

Abstract EN

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is one of the major receptors expressed on the endothelium of arterial wall with a key role in endothelial dysfunction and the development of atherosclerosis.

Recent evidence suggested that LOX-1 is upregulated under the condition of insulin resistance and could be suppressed by the antidiabetic drugs.

We previously also confirmed that Thiazolidinedione (TZD) has the inhibitory effect on LOX-1 in ox-LDL-induced endothelial cells.

However, the underlying mechanism is unclear.

Here we showed that Rosiglitazone treatment significantly attenuated the expressions of LOX-1, ICAM-1, VCAM-1, p 4 7 p h o x , and the atherosclerotic lesions in ApoE-/- mice with high-fat diet.

In vitro, we revealed that Rosiglitazone inhibited LOX-1 by regulating miR-590-5p.

Ox-LDL-mediated ICAM-1, VCAM-1, and p 4 7 p h o x were significantly reduced by Rosiglitazone, but all reversed after pretreating the cells with antagomiR-590-5p.

Induction with Rosiglitazone activated PPAR-γ and promoted its nuclear translocation in cultured human umbilical vein endothelial cells (HUVECs).

The nuclear PPAR-γ upregulated the miR-590-5p level through binding to its transcriptional promoter region.

Retaining PPAR-γ in cytoplasm by transfecting with P P A R - γ ⊿ N L S plasmid in HUVECs failed to activate miR-590-5p.

Mutation of the promoter region of PPAR-γ also reduced the miR-590-5p promoter luciferase activity.

Collectively, these data indicated that PPAR-γ may have the therapeutic potential in atherosclerosis via the transcriptional regulation of miR-590-5p in endothelial cells.