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Published on: September 26, 2018
MicroRNA-216a Promotes Endothelial Inflammation by Smad7/IκBα Pathway in Atherosclerosis
Shujun Yang1,2, Yu Chen1, Xuenan Mi1
1State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China.
Background:
The endothelium is the first line of defence against harmful microenvironment risks, and microRNAs (miRNAs) involved in vascular inflammation may be promising therapeutic targets to modulate atherosclerosis progression. In this study, we aimed to investigate the mechanism by which microRNA-216a (miR-216a) modulated inflammation activation of endothelial cells. Methods. A replicative senescence model of human umbilical vein endothelial cells (HUVECs) was established, and population-doubling levels (PDLs) were defined during passages. PDL8 HUVECs were transfected with miR-216a mimics/inhibitor or small interfering RNA (siRNA) of SMAD family member 7 (Smad7). Real-time PCR and Western blot assays were performed to detect the regulatory role of miR-216a on Smad7 and NF-κB inhibitor alpha (IκBα) expression. The effect of miR-216a on adhesive capability of HUVECs to THP-1 cells was examined. MiR-216a and Smad7 expression in vivo were measured using human carotid atherosclerotic plaques of the patients who underwent carotid endarterectomy (n = 41).
Results:
Luciferase assays showed that Smad7 was a direct target of miR-216a. Smad7 mRNA expression, negatively correlated with miR-216a during endothelial aging, was downregulated in senescent PDL44 cells, compared with young PDL8 HUVECs. MiR-216a markedly increased endothelial inflammation and adhesive capability to monocytes in PDL8 cells by promoting the phosphorylation and degradation of IκBα and then activating NF-κB signalling pathway. The effect of miR-216a on endothelial cells was consistent with that blocked Smad7 by siRNAs. When inhibiting endogenous miR-216a, the Smad7/IκBα expression was rescued, which led to decreased endothelial inflammation and monocytes recruitment. In human carotid atherosclerotic plaques, Smad7 level was remarkably decreased in high miR-216a group compared with low miR-216a group. Moreover, miR-216a was negatively correlated with Smad7 and IκBα levels and positively correlated with interleukin 1 beta (IL1β) expression in vivo.
Conclusion:
In summary, our findings suggest a new mechanism of vascular endothelial inflammation involving Smad7/IκBα signalling pathway in atherosclerosis.
Insights
MicroRNA-216a promotes vascular endothelial inflammation and monocyte adhesion by targeting Smad7 and activating the NF-κB pathway. Inhibiting miR-216a reduces inflammation, suggesting a new therapeutic target for atherosclerosis.
Area of Science:
- Vascular Biology
- Molecular Medicine
- Atherosclerosis Research
Background:
- The endothelium acts as a defense against microenvironmental risks.
- MicroRNAs (miRNAs) are implicated in vascular inflammation and atherosclerosis.
- Investigating specific miRNAs like microRNA-216a (miR-216a) is crucial for understanding endothelial cell activation.
Purpose of the Study:
- To elucidate the mechanism by which miR-216a modulates inflammation in endothelial cells.
- To determine the role of miR-216a in endothelial aging and monocyte adhesion.
- To explore the relationship between miR-216a, Smad7, and the NF-κB pathway in atherosclerosis.
Main Methods:
- Established a replicative senescence model using human umbilical vein endothelial cells (HUVECs).
- Utilized miR-216a mimics/inhibitors and siRNA against SMAD family member 7 (Smad7).
- Performed real-time PCR, Western blot, luciferase assays, and analyzed human carotid atherosclerotic plaques.
Main Results:
- Smad7 was identified as a direct target of miR-216a.
- miR-216a promoted endothelial inflammation and monocyte adhesion by downregulating Smad7, leading to IκBα degradation and NF-κB activation.
- In vivo studies showed decreased Smad7 and increased miR-216a, IL1β in atherosclerotic plaques, correlating with disease severity.
Conclusions:
- miR-216a plays a significant role in vascular endothelial inflammation via the Smad7/IκBα/NF-κB signaling pathway.
- This pathway represents a novel mechanism contributing to atherosclerosis progression.
- Targeting miR-216a could offer a potential therapeutic strategy for atherosclerosis.
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