Noncoding RNAs regulate NF-κB signaling to modulate blood vessel inflammation

Abstract

Cardiovascular diseases such as atherosclerosis are one of the leading causes of morbidity and mortality worldwide. The clinical manifestations of atherosclerosis, which include heart attack and stroke, occur several decades after initiation of the disease and become more severe with age. Inflammation of blood vessels plays a prominent role in atherogenesis. Activation of the endothelium by inflammatory mediators leads to the recruitment of circulating inflammatory cells, which drives atherosclerotic plaque formation and progression. Inflammatory signaling within the endothelium is driven predominantly by the pro-inflammatory transcription factor, NF-κB. Interestingly, activation of NF-κB is enhanced during the normal aging process and this may contribute to the development of cardiovascular disease. Importantly, studies utilizing mouse models of vascular inflammation and atherosclerosis are uncovering a network of noncoding RNAs, particularly microRNAs, which impinge on the NF-κB signaling pathway. Here we summarize the literature regarding the control of vascular inflammation by microRNAs, and provide insight into how these microRNA-based pathways might be harnessed for therapeutic treatment of disease. We also discuss emerging areas of endothelial cell biology, including the involvement of long noncoding RNAs and circulating microRNAs in the control of vascular inflammation.

Keywords: NF-κB; atherosclerosis; endothelial activation; gene regulation; inflammation; noncoding RNA; post-transcriptional; signaling.

FIGURE 1

A network of noncoding RNAs negatively regulates NF-κB signaling. A key mediator of endothelial cell (EC) activation and vascular inflammation is the transcription factor, NF-κB. In non-stimulated cells, NF-κB subunits (e.g., p65/p50) are sequestered in the cytoplasm through their interaction with IκB. In response to inflammatory signaling, the IKK complex phosphorylates IκB, which is then ubiquitylated by β-TRC, leading to its degradation. This results in the release of NF-κB, allowing it to enter the nucleus and bind to its transcriptional targets, which include leukocyte adhesion molecules, chemokines, and cytokines. NF-κB-dependent microRNAs, such as miR-146a and miR-155 impinge on various stages of the NF-κB signaling pathway, and play critical roles in attenuating activation of this pathway. The microRNA targets that have been verified in ECs are shown as solid lines, and targets validated in other cell types are indicated with dashed lines. Flow dynamics play a crucial role in regulating EC activation. Laminar flow initiates an anti-inflammatory gene expression program that includes up-regulation of transcription factors such as KLF2 and KLF4 that not only promote the expression of anti-inflammatory genes, but also compete with NF-κB for access to the transcriptional co-activator, p300. Laminar flow promotes the expression of miR-10a, which negatively regulates NF-κB activity in ECs by directly targeting TAK1 and β-TRC. In contrast, oscillatory flow induces - while laminar flow suppresses - the expression of miR-92a, which targets KLF2 and KLF4, leading to increased inflammation. MicroRNAs can be found at high levels within microvesicles (MVs) in the circulation. The effects of MVs on EC inflammatory pathways are not known, but may include regulation of signaling pathways or transfer of microRNAs to ECs. Long noncoding RNAs (lncRNA) have recently been shown to regulate NF-κB signaling in other cells types, but their effects on EC inflammatory pathways are not yet known.