Abstract
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, p47phox, 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 p47phox 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 PPAR-γ⊿NLS 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.
Highlights
Endothelial oxidative injury is considered as the leading cause of coronary atherosclerosis, and oxidized low-density lipoprotein cholesterol is critically involved in endothelial oxidative injury and dysfunction [1]
Accompanied by the upregulation of lipoprotein receptor-1 (LOX-1), high-fat diet increased the expressions of ICAM-1, VCAM-1, and p47phox in ApoE−/− mice, which were all reversed by Rosiglitazone treatment (Figures 1(e)–1(h)), suggesting that Peroxisome proliferator activated receptors (PPARs)-γ activation might effectively suppress LOX-1 expression and prevent endothelial inflammation and oxidative injury during the development of atherosclerosis
This study demonstrates that Rosiglitazone treatment effectively protects the high-fat diet-induced ApoE−/− mice through reducing the occurrence and development of atherosclerosis
Summary
Endothelial oxidative injury is considered as the leading cause of coronary atherosclerosis, and oxidized low-density lipoprotein cholesterol (ox-LDL) is critically involved in endothelial oxidative injury and dysfunction [1]. Lectinlike oxidized low-density lipoprotein receptor-1 (LOX-1) is the major scavenger receptor for Ox-LDL, which promotes the uptake of ox-LDL by endothelial cells (ECs) in the arterial wall, and accelerates the process of inflammation and oxidative stress [1, 2]. The basal line of LOX-1 in ECs is very low, but it can be rapidly induced by prooxidative stress, such as ox-LDL, angiotensin II (AngII), advanced glycation end productions (AGEs), and proinflammatory cytokines [2,3,4]. The activation of LOX-1 promotes EC uptake of large amounts of ox-LDL, leads to apoptosis of vascular endothelial and smooth muscle cells, increases the production of matrix metalloproteinases and intercellular adhesion molecules, which promotes migration and infiltration of inflammatory cells, and accelerates the atherosclerotic progression and plaque vulnerability [2, 5]. The wide spectrum effects of PPAR-γ activation may be beneficial for lipid metabolism, promoting free fatty acid
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