Extracellular Uridine Triphosphate and Adenosine Triphosphate Attenuate Endothelial Inflammation through miR-22-Mediated ICAM-1 Inhibition

Abstract

Adenosine and uridine triphosphate (ATP and UTP) can act as extracellular signalling molecules, playing important roles in vascular biology and disease. ATP and UTP acting via the P2Y₂-receptor have, for example, been shown to regulate endothelial dilatation, inflammation and angiogenesis. MicroRNAs (miRNAs), a class of regulatory, short, non-coding RNAs, have been shown to be important regulators of these biological processes. In this study, we used RNA deep-sequencing to explore changes in miRNA expression in the human microvascular endothelial cell line HMEC-1 upon UTP treatment. The expression of miR-22, which we have previously shown to target ICAM-1 mRNA in HMEC-1, increased significantly after stimulation. Up-regulation of miR-22 and down-regulation of cell surface ICAM-1 were confirmed with qRT-PCR and flow cytometry, respectively. siRNA-mediated knockdown of the P2Y₂-receptor abolished the effect of UTP on miR-22 transcription. Leukocyte adhesion was significantly inhibited in HMEC-1 following miR-22 overexpression and treatment with UTP/ATP. In conclusion, extracellular UTP and ATP can attenuate ICAM-1 expression and leukocyte adhesion in endothelial cells through miR-22.

MicroRNA‐22 regulates inflammation and angiogenesis via targeting VE‐cadherin

“…In the inflammatory cells stimulated by Poly (I:C), miR‐22 expression is significantly downregulated, suggesting that miR‐22 may participate in host inflammatory response, which is consistent with its regulation of ICAM‐1 expression . Overexpression of miR‐22 induces the inflammation with increased cytokine synthesis (IL‐1β, IL‐6, and IL‐8) in endothelial cells.…”

“…Our study suggests that miR‐22 is able to regulate the VE‐cadherin in zebrafish, mice, and humans. The reported miR‐22‐targeting molecules include a list of proteins, such as estrogen receptor α , PTEN , histone deacetylase 4 , CD147 , T‐cell lymphoma invasion and metastasis 1 , matrix metalloproteinases 2 and 9 , AKT3 , ICAM‐1 , and sirtuin 1 , our results clearly indicate that miR‐22 also directly targets VE‐cadherin and regulates its gene expression in endothelial cells.…”

“…Given the importance of miR‐22 in tumor metastasis and cardiovascular functions, understanding its role in endothelial cells is necessary. Although mir‐22 induces endothelial progenitor cell senescence and inhibits ATP‐ or UTP‐induced intercellular adhesion molecule‐1 (ICAM‐1) expression , its function and targeting molecules in endothelial cells need further investigation.…”

Differentially expressed non-coding RNAs induced by transmissible gastroenteritis virus potentially regulate inflammation and NF-κB pathway in porcine intestinal epithelial cell line

“…In the present study, we demonstrated that TGEV infection activated inflammation-related pathways and up-regulated miR-22. It was reported that miR-22 was involved in regulating inflammation and immune response [18,19]. Therefore, we speculated that miR-22 might play a role in TGEV-induced inflammation response.…”

Endothelial microRNAs regulating the NF‐κB pathway and cell adhesion molecules during inflammation

“…In this study, ATP and uridine triphosphate (UTP) increase the transcription of miR-22 by acting as extracellular signaling molecules and transduce signals through purinergic receptor P2Y2. In vitro, ATP and UTP alleviate epithelial ICAM-1 expression and leukocyte adhesion through up-regulating miR-22 (59). Whether this mechanism is conserved in endothelial cells warrants further investigation.…”