Endothelial Dicer promotes atherosclerosis and vascular inflammation by miRNA-103-mediated suppression of KLF4

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.

A non-coding function of TYRP1 mRNA promotes melanoma growth

“…miRCURY LNA TSBs were designed by Exiqon [39][40][41] . TSB-T3 selectively binds to a sequence overlapping the MRE-16 no.…”

“…Having demonstrated that TYRP1 mRNA dampens miR-16 activity, we challenged this sequestration model with small antisense oligonucleotides, known as target site blockers (TSBs) [39][40][41] . We designed two TSBs of 16 nucleotides in length: a control TSB (TSB-C1) that does not match any annotated human 3 UTR and a functional TSB (TSB-T3) that selectively binds to the sequence overlapping the TYRP1 MRE-16 site (2392-2407).…”

Effect of endothelial microRNAs on blood pressure homeostasis

“…Previous studies have demonstrated that endothelial miRNAs control endothelial functions and are implicated in the onset and development of cardiovascular disease 9,[19][20][21][22] . However, the role of endothelial miRNAs in BP homeostasis has been poorly understood.…”

“…However, the remaining Dicer1 allele might compensate for the phenotype of hemodynamics in EC-specific Dicer heterozygous KO mice. It has been reported that miRNAs are important regulators in cardiovascular diseases such as atherosclerosis and abdominal aortic aneurysms and potential therapeutic candidates regarding these diseases 9,20) . Therefore, further studies are needed to investigate the role of endothelial miRNA-mediated post-transcriptional gene regulation in the maintenance of BP homeostasis.…”

“…It has been reported that the knockdown of Dicer increased endothelial nitric oxide synthase (eNOS) protein expression and affected cell proliferation and tube formation in human umbilical vein endothelial cells (HUVEC) 8) . Moreover, the EC-specific deletion of Dicer1 in atherosclerosis prone ApoE KO mice inhibited the progression of atherosclerosis 9) . These evidence suggests that the endothelial miRNAs are potential regulators of cardiovascular biology and disease.…”