Intermittent hypoxia increased the expression of ESM1 and ICAM‐1 in vascular endothelial cells via the downregulation of microRNA‐181a1

Abstract

Sleep apnea syndrome (SAS) exposes cells throughout the body to intermittent hypoxia (IH). Intermittent hypoxia is a risk factor not only for hypertension and insulin resistance but also for vascular dysfunction. We have reported correlations between IH, insulin resistance and hypertension. However, the details of why IH leads to vascular dysfunction remain unclear. In this study, we investigated inflammation‐related transcripts in vascular endothelial cells (human HUEhT‐1 and mouse UV2) exposed to IH by real‐time RT‐PCR and found that intercellular adhesion molecule‐1 (ICAM‐1) and endothelial cell‐specific molecule‐1 (ESM1) mRNAs were significantly increased. ELISA confirmed that, in the UV2 cell medium, ICAM‐1 and ESM1 were significantly increased by IH. However, the promoter activities of ICAM‐1 and ESM1 were not upregulated. On the other hand, IH treatment significantly decreased microRNA (miR)‐181a1 in IH‐treated cells. The introduction of miR‐181a1 mimic but not miR‐181a1 mimic NC abolished the IH‐induced upregulation of Ican‐1 and ESM1. These results indicated that ICAM‐1 and ESM1 were upregulated by IH via the IH‐induced downregulation of miR‐181a1 in vascular endothelial cells and suggested that SAS patients developed atherosclerosis via the IH‐induced upregulation of ICAM‐1 and ESM1.

Possible Molecular Mechanisms of Hypertension Induced by Sleep Apnea Syndrome/Intermittent Hypoxia

“…We conducted additional investigation into the pathways through which IH increased the mRNA levels of both Icam-1 and Esm1. We also identified a potential post-transcriptional mechanism involving miR-181a1-mediated expression [133] (Figure 5).…”

“…Therefore, the increases in pro-inflammatory and inflammatory cytokines such as IL-1β, IL-6, and IL-8 in monocytes lead to systemic inflammation and worsen metabolic syndrome, including hypertension in SAS patients (Figure 6). It is suggested that, in patients with SAS, the increased expression of Esm1 and Icam-1 in vascular endothelial cells may contribute to the development of vascular endothelial dysfunction, while miR-181a1 may have a significant impact on the modulation of these gene expressions [133]. The up and down arrows next to the name indicate increase and decrease, respectively.…”

“…Possible mechanism of vascular endothelial dysfunction induced by IH. The downregulation of miR-181a1 in IH-treated vascular endothelial cells increased gene expression for Esm1 and Icam-1.It is suggested that, in patients with SAS, the increased expression of Esm1 and Icam-1 in vascular endothelial cells may contribute to the development of vascular endothelial dysfunction, while miR-181a1 may have a significant impact on the modulation of these gene expressions[133]. The up and down arrows next to the name indicate increase and decrease, respectively.…”