Abstract
The transcription factor NF-κB has an essential role in inflammation in endothelial cells. Endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) prevents vascular inflammation. However, the molecular mechanism underlying NF-κB-mediated regulation of eNOS expression has not been clearly elucidated. We here found that NF-κB-activating stimuli, such as lipopolysaccharide, tumor necrosis factor-α (TNF-α), and interleukin-1β, suppressed eNOS mRNA and protein levels by decreasing mRNA stability, without affecting promoter activity. TNF-α-mediated suppression of eNOS expression, mRNA stability, and 3′-untranslated region (3′UTR) activity were inhibited by NF-κB inhibitors and Dicer knockdown, but not by p38 MAPK and MEK inhibitors, suggesting the involvement of NF-κB-responsive miRNAs in eNOS expression. Moreover, TNF-α increased MIR155HG expression and promoter activity as well as miR-155 biogenesis, and these increases were blocked by NF-κB inhibitors. Transfection with antagomiR-155 blocked TNF-α-mediated suppression of eNOS 3′UTR activity, eNOS mRNA and protein levels, and NO and cGMP production. These data provide evidence that NF-κB is a negative regulator of eNOS expression via upregulation of miR-155 under inflammatory conditions. These results suggest that NF-κB is a potential therapeutic target for preventing vascular inflammation and endothelial dysfunction induced by suppression of miR-155-mediated eNOS expression.
| Original language | English |
|---|---|
| Pages (from-to) | 101-107 |
| Number of pages | 7 |
| Journal | Biochemical and Biophysical Research Communications |
| Volume | 448 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2014 May 23 |
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All Science Journal Classification (ASJC) codes
- Biophysics
- Biochemistry
- Molecular Biology
- Cell Biology
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Functional role of NF-κB in expression of human endothelial nitric oxide synthase. / Lee, Kyu Sun; Kim, Joohwan; Kwak, Su Nam; Lee, Kwang Soon; Lee, Dong Keon; Ha, Kwon Soo; Won, Moo Ho; Jeoung, Dooil; Lee, Hansoo; Kwon, Young-Guen; Kim, Young Myeong.
In: Biochemical and Biophysical Research Communications, Vol. 448, No. 1, 23.05.2014, p. 101-107.Research output: Contribution to journal › Article
TY - JOUR
T1 - Functional role of NF-κB in expression of human endothelial nitric oxide synthase
AU - Lee, Kyu Sun
AU - Kim, Joohwan
AU - Kwak, Su Nam
AU - Lee, Kwang Soon
AU - Lee, Dong Keon
AU - Ha, Kwon Soo
AU - Won, Moo Ho
AU - Jeoung, Dooil
AU - Lee, Hansoo
AU - Kwon, Young-Guen
AU - Kim, Young Myeong
PY - 2014/5/23
Y1 - 2014/5/23
N2 - The transcription factor NF-κB has an essential role in inflammation in endothelial cells. Endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) prevents vascular inflammation. However, the molecular mechanism underlying NF-κB-mediated regulation of eNOS expression has not been clearly elucidated. We here found that NF-κB-activating stimuli, such as lipopolysaccharide, tumor necrosis factor-α (TNF-α), and interleukin-1β, suppressed eNOS mRNA and protein levels by decreasing mRNA stability, without affecting promoter activity. TNF-α-mediated suppression of eNOS expression, mRNA stability, and 3′-untranslated region (3′UTR) activity were inhibited by NF-κB inhibitors and Dicer knockdown, but not by p38 MAPK and MEK inhibitors, suggesting the involvement of NF-κB-responsive miRNAs in eNOS expression. Moreover, TNF-α increased MIR155HG expression and promoter activity as well as miR-155 biogenesis, and these increases were blocked by NF-κB inhibitors. Transfection with antagomiR-155 blocked TNF-α-mediated suppression of eNOS 3′UTR activity, eNOS mRNA and protein levels, and NO and cGMP production. These data provide evidence that NF-κB is a negative regulator of eNOS expression via upregulation of miR-155 under inflammatory conditions. These results suggest that NF-κB is a potential therapeutic target for preventing vascular inflammation and endothelial dysfunction induced by suppression of miR-155-mediated eNOS expression.
AB - The transcription factor NF-κB has an essential role in inflammation in endothelial cells. Endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) prevents vascular inflammation. However, the molecular mechanism underlying NF-κB-mediated regulation of eNOS expression has not been clearly elucidated. We here found that NF-κB-activating stimuli, such as lipopolysaccharide, tumor necrosis factor-α (TNF-α), and interleukin-1β, suppressed eNOS mRNA and protein levels by decreasing mRNA stability, without affecting promoter activity. TNF-α-mediated suppression of eNOS expression, mRNA stability, and 3′-untranslated region (3′UTR) activity were inhibited by NF-κB inhibitors and Dicer knockdown, but not by p38 MAPK and MEK inhibitors, suggesting the involvement of NF-κB-responsive miRNAs in eNOS expression. Moreover, TNF-α increased MIR155HG expression and promoter activity as well as miR-155 biogenesis, and these increases were blocked by NF-κB inhibitors. Transfection with antagomiR-155 blocked TNF-α-mediated suppression of eNOS 3′UTR activity, eNOS mRNA and protein levels, and NO and cGMP production. These data provide evidence that NF-κB is a negative regulator of eNOS expression via upregulation of miR-155 under inflammatory conditions. These results suggest that NF-κB is a potential therapeutic target for preventing vascular inflammation and endothelial dysfunction induced by suppression of miR-155-mediated eNOS expression.
UR - http://www.scopus.com/inward/record.url?scp=84901188380&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84901188380&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2014.04.079
DO - 10.1016/j.bbrc.2014.04.079
M3 - Article
C2 - 24769202
AN - SCOPUS:84901188380
VL - 448
SP - 101
EP - 107
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 1
ER -