MicroRNA-10a regulation of proinflammatory phenotype in athero-susceptible endothelium in vivo and in vitro

Abstract

A chronic proinflammatory state precedes pathological change in arterial endothelial cells located within regions of susceptibility to atherosclerosis. The potential contributions of regulatory microRNAs to this disequilibrium were investigated by artery site-specific profiling in normal adult swine. Expression of endothelial microRNA10a (miR-10a) was lower in the athero-susceptible regions of the inner aortic arch and aorto-renal branches than elsewhere. Expression of Homeobox A1 (HOXA1), a known miR-10a target, was up-regulated in the same locations. Endothelial transcriptome microarray analysis of miR-10a knockdown in cultured human aortic endothelial cells (HAEC) identified IκB/NF-κB-mediated inflammation as the top category of up-regulated biological processes. Phosphorylation of IκBα, a prerequisite for IκBα proteolysis and NF-κB activation, was significantly up-regulated in miR-10a knockdown HAEC and was accompanied by increased nuclear expression of NF-κB p65. The inflammatory biomarkers monocyte chemotactic protein 1 (MCP-1), IL-6, IL-8, vascular cell adhesion molecule 1 (VCAM-1), and E-selectin were elevated following miR-10a knockdown. Conversely, knockin of miR10a (a conservative 25-fold increase) inhibited the basal expression of VCAM-1 and E-selectin in HAEC. Two key regulators of IκBα degradation-mitogen-activated kinase kinase kinase 7 (MAP3K7; TAK1) and β-transducin repeat-containing gene (βTRC)-contain a highly conserved miR-10a binding site in the 3′ UTR. Both molecules were up-regulated by miR-10a knockdown and suppressed by miR-10a knockin, and evidence of direct miR-10a binding to the 3′ UTR was demonstrated by luciferase assay. Comparative expression studies of endothelium located in athero-susceptible aortic arch and athero-protected descending thoracic aorta identified significantly up-regulated MAP3K7, βTRC, phopho-IκBα, and nuclear p65 expression suggesting that the differential expression of miR-10a contributes to the regulation of proinflammatory endothelial phenotypes in athero-susceptible regions in vivo.β-transducing repeat-containing gene | hemodynamics | mitogen-activated kinase kinase kinase 7 | NF-κB

MicroRNA-10a is crucial for endothelial response to different flow patterns via interaction of retinoid acid receptors and histone deacetylases

“…miR-10a was recently found to be the miR with the lowest expression among 1,139 miRs in endothelia of atherosusceptible regions vs. atheroprotected regions in normal adult swine in vivo. Knockdown of miR-10a in human aortic ECs exerts a proinflammatory phenotype in vitro (7). We compared EC expression of miR-10a with that of other mechano-miRs, including miR-126-5p, -145, -148a, -126, -155, -19a, -101, -23b, -21, -92a, and -663, under different flow conditions, and confirmed that miR-10a is the miR with the lowest expression among all EC mechano-miRs examined in response to OS.…”

“…miR-10a has been identified as the miR with the lowest expression among 1,139 miRs, including miR-92a, miR-21, and miR-221, in the endothelium of atherosusceptible regions [inner curvature of the aortic arch (AA)] vs. atheroprotected regions [descending thoracic aorta (TA)] in normal adult swine in vivo, and it inhibits the proinflammatory endothelial phenotype in vitro (7). However, whether different hemodynamic forces play differential roles in regulating miR-10a expression, and the detailed mechanisms involved in these regulations, remain unclear.…”

Shear stress activation of nuclear receptor PXR in endothelial detoxification

“…qRT-PCR demonstrated that the mRNA level of MDR1 was significantly higher in endothelium from the rat descending thoracic aorta (TA), where flow is mostly laminar, than those from the inner curvature of aortic arch (AA), where flow is disturbed (16) (Fig. 1F).…”

The atypical mechanosensitive microrna-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis

“…LS stimulates expression of miR-10a, miR-19a, miR-21, miR-23b, miR-101, and miR-143/145, mediating anti-atherogenic events 37,38,39,40,41,42 , while OS induces expression of miR-21, miR-92a, and miR-663 leading to proatherogenic responses 14,43,44 . miR-155 is also flow-sensitive miRNA but its role in atherosclerosis is controversial 45 .…”