526The role of endothelial Dicer in atherosclerosis

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Abstract

Background: Increased monocyte adhesion to dysfunctional endothelial cells (ECs) orchestrated by chemokines plays an important role in atherosclerosis. Endothelial microRNAs (miRNAs) processed by the RNase Dicer determine the phenotype of ECs by posttranscriptional regulation of gene expression. However, the impact of endothelial miRNAs on endothelial inflammation and atherosclerosis is currently unclear.

Methods: VE-Cadherin-CreERT2/Dicerflox/flox/Apoe-/- (EC-Dicerflox) and VE-Cadherin-CreERT2/DicerWT/WT/Apoe-/- (EC-DicerWT) mice were treated with tamoxifen to induce the activity of Cre-recombinase and fed with a high fat diet for 4 or 12 weeks (wks). The plaque area in aortic roots was analyzed by morphometry in Elasic Van Gieson stained sections. The lipid deposition was determined in en face prepared thoracoabdominal aortas by Oil-Red-O staining. To study monocyte adhesion to the endothelium, left carotid arteries of EC-Dicerflox and EC-DicerWT were ex vivo perfused with calcein-AM labeled monocytic MonoMac6 cells at a flow rate of 0.1 ml/min. Differentially expressed miRNAs in EC-Dicerflox and EC-DicerWT aortas were identified by qRT-PCR microRNA arrays.

Results: In EC-Dicerflox mice, the adhesion of monocytes and expression of chemokines, such as CXCL1, was reduced in carotid arteries after 4wks HFD feeding (n=5-6; p<0.01; p<0.05). Atherosclerosis in aortic roots (by 58%) and lipid depositions in thoracoabdominal aortas (by 41%) were diminished in EC-Dicerflox compared to EC-DicerWT mice after 12wks HFD feeding (n=8-9; p<0.05; p<0.01). Moreover, the lesional macrophage content in the aorta was reduced in EC-Dicerflox (n=8-9; p<0.01). Mir103, -301b, -433, and -652 were permanently down-regulated after 4 and 12wks of the HFD in arteries of EC-Dicerflox mice (n=3; p<0.05). In vitro, only the expression of Mir103 was correlated with the expression of chemokines in human aortic ECs (HAoECs) and Mir103 regulated CXCL1 expression in HAoECs by targeting the anti-inflammatory transcription factor Kruppel-like factor (KLF) 4 (n=5; p<0.05). Accordingly, treatment of HAoECs with Mir103 enhanced monocyte adhesion in a CXCR2-dependent manner (n=3; p<0.001).

Conclusion: Our findings indicate that endothelial Dicer promotes atherosclerosis by enhancing monocyte recruitment to the endothelium. This effect is at least partly due to endothelial Mir103, which up-regulates CXCL1 by targeting KLF4. Therefore, inhibition of Mir103 might be a promising therapeutic approach to treat atherosclerosis.

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