Abstract
MicroRNAs regulate the maladaptation of endothelial cells (ECs) to naturally occurring disturbed blood flow at arterial bifurcations resulting in arterial inflammation and atherosclerosis in response to hyperlipidemic stress. Here, we show that reduced endothelial expression of the RNAse Dicer, which generates almost all mature miRNAs, decreases monocyte adhesion, endothelial C–X–C motif chemokine 1 (CXCL1) expression, atherosclerosis and the lesional macrophage content in apolipoprotein E knockout mice (Apoe−/−) after exposure to a high-fat diet. Endothelial Dicer deficiency reduces the expression of unstable miRNAs, such as miR-103, and promotes Krüppel-like factor 4 (KLF4)-dependent gene expression in murine atherosclerotic arteries. MiR-103 mediated suppression of KLF4 increases monocyte adhesion to ECs by enhancing nuclear factor-κB-dependent CXCL1 expression. Inhibiting the interaction between miR-103 and KLF4 reduces atherosclerosis, lesional macrophage accumulation and endothelial CXCL1 expression. Overall, our study suggests that Dicer promotes endothelial maladaptation and atherosclerosis in part by miR-103-mediated suppression of KLF4.
Highlights
MicroRNAs regulate the maladaptation of endothelial cells (ECs) to naturally occurring disturbed blood flow at arterial bifurcations resulting in arterial inflammation and atherosclerosis in response to hyperlipidemic stress
Many miRNAs are downregulated in atherosclerotic arteries[26], Dicer expression in the aortas of Apoe–/– mice was not affected by 12 weeks of high-fat diet (HFD) feeding compared with mice fed a normal diet (Supplementary Fig. 1a), indicating that miRNA biogenesis by Dicer is not generally impaired during early atherosclerosis
In ECs isolated from the aortas of EC-Dicerflox mice injected with TMX, Dicer mRNA expression was decreased by 87% compared with ECs isolated from EC-DicerWT mice (Fig. 1b), whereas the expression of Dicer was not affected in myeloid cells from EC-Dicerflox mice (Supplementary Fig. 1d)
Summary
MicroRNAs regulate the maladaptation of endothelial cells (ECs) to naturally occurring disturbed blood flow at arterial bifurcations resulting in arterial inflammation and atherosclerosis in response to hyperlipidemic stress. We show that reduced endothelial expression of the RNAse Dicer, which generates almost all mature miRNAs, decreases monocyte adhesion, endothelial C–X–C motif chemokine 1 (CXCL1) expression, atherosclerosis and the lesional macrophage content in apolipoprotein E knockout mice (Apoe–/–) after exposure to a high-fat diet. Endothelial Dicer deficiency reduces the expression of unstable miRNAs, such as miR-103, and promotes Kruppel-like factor 4 (KLF4)-dependent gene expression in murine atherosclerotic arteries. MiR-103 mediated suppression of KLF4 increases monocyte adhesion to ECs by enhancing nuclear factor-kB-dependent CXCL1 expression. EC-specific deletion of Dicer in apolipoprotein E-knockout (Apoe–/–) mice reduced monocyte adhesion to the early atherosclerotic endothelium by downregulating CXCL1, resulting in diminished lesion formation. These data indicate that Dicer can enhance atherosclerosis and endothelial inflammation by increasing miR-103 expression
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