TY - JOUR
T1 - MicroRNA-30 mediates anti-inflammatory effects of shear stress and KLF2 via repression of angiopoietin 2
AU - Demolli, Shemsi
AU - Doebele, Carmen
AU - Doddaballapur, Anuradha
AU - Lang, Victoria
AU - Fisslthaler, Beate
AU - Chavakis, Emmanouil
AU - Vinciguerra, Manlio
AU - Sciacca, Sergio
AU - Henschler, Reinhard
AU - Hecker, Markus
AU - Savant, Soniya
AU - Augustin, Hellmut G.
AU - Kaluza, David
AU - Dimmeler, Stefanie
AU - Boon, Reinier A.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - MicroRNAs are endogenously expressed small noncoding RNAs that regulate gene expression. Laminar blood flow induces atheroprotective gene expression in endothelial cells (ECs) in part by upregulating the transcription factor KLF2. Here, we identified KLF2- and flow-responsive miRs that affect gene expression in ECs. Bioinformatic assessment of mRNA expression patterns identified the miR-30-5p seed sequence to be highly enriched in mRNAs that are downregulated by KLF2. Indeed, KLF2 overexpression and shear stress stimulation in vitro and in vivo increased the expression of miR-30-5p family members. Furthermore, we identified angiopoietin 2 (Ang2) as a target of miR-30. MiR-30 overexpression reduces Ang2 levels, whereas miR-30 inhibition by LNA-antimiRs induces Ang2 expression. Consistently, miR-30 reduced basal and TNF-a-induced expression of the inflammatory cell-cell adhesion molecules E-selectin, ICAM1 and VCAM1, which was rescued by stimulation with exogenous Ang2. In summary, KLF2 and shear stress increase the expression of the miR-30-5p family which acts in an antiinflammatory manner in ECs by impairing the expression of Ang2 and inflammatory cell-cell adhesion molecules. The upregulation of miR-30-5p family members may contribute to the atheroprotective effects of shear stress.
AB - MicroRNAs are endogenously expressed small noncoding RNAs that regulate gene expression. Laminar blood flow induces atheroprotective gene expression in endothelial cells (ECs) in part by upregulating the transcription factor KLF2. Here, we identified KLF2- and flow-responsive miRs that affect gene expression in ECs. Bioinformatic assessment of mRNA expression patterns identified the miR-30-5p seed sequence to be highly enriched in mRNAs that are downregulated by KLF2. Indeed, KLF2 overexpression and shear stress stimulation in vitro and in vivo increased the expression of miR-30-5p family members. Furthermore, we identified angiopoietin 2 (Ang2) as a target of miR-30. MiR-30 overexpression reduces Ang2 levels, whereas miR-30 inhibition by LNA-antimiRs induces Ang2 expression. Consistently, miR-30 reduced basal and TNF-a-induced expression of the inflammatory cell-cell adhesion molecules E-selectin, ICAM1 and VCAM1, which was rescued by stimulation with exogenous Ang2. In summary, KLF2 and shear stress increase the expression of the miR-30-5p family which acts in an antiinflammatory manner in ECs by impairing the expression of Ang2 and inflammatory cell-cell adhesion molecules. The upregulation of miR-30-5p family members may contribute to the atheroprotective effects of shear stress.
KW - Angiopoietin
KW - Endothelial cell
KW - KLF2
KW - Laminar shear stress
KW - MicroRNA
UR - http://www.scopus.com/inward/record.url?scp=84944042723&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2015.10.009
DO - 10.1016/j.yjmcc.2015.10.009
M3 - Article
C2 - 26456066
AN - SCOPUS:84944042723
VL - 88
SP - 111
EP - 119
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
ER -