Short communication: asymmetric dimethylarginine impairs angiogenic progenitor cell function in patients with coronary artery disease through a microRNA-21-dependent mechanism.
BACKGROUND
The endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) is increased in patients with coronary artery disease and may regulate function of circulating angiogenic progenitor cells (APCs) by small regulatory RNAs.


OBJECTIVE
To study the role of microRNAs in ADMA-mediated impairment of APCs.


RESULTS
By using microarray analyses, we established microRNA expression profiles of human APCs. We used ADMA to induce APC dysfunction and found 16 deregulated microRNAs. We focused on miR-21, which was 3-fold upregulated by ADMA treatment. Overexpression of miR-21 in human APCs impaired migratory capacity. To identify regulated miR-21 targets, we used proteome analysis, using difference in-gel electrophoresis followed by mass spectrometric analysis of regulated proteins. We found that transfection of miR-21 precursors significantly repressed superoxide dismutase 2 in APCs, which resulted in increased intracellular reactive oxygen species concentration and impaired nitric oxide bioavailability. MiR-21 further repressed sprouty-2, leading to Erk Map kinase-dependent reactive oxygen species formation and APC migratory defects. Small interference RNA-mediated superoxide dismutase 2 or sprouty-2 reduction also increased reactive oxygen species formation and impaired APC migratory capacity. ADMA-mediated reactive oxygen species formation and APC dysfunction was rescued by miR-21 blockade. APCs from patients with coronary artery disease and high ADMA plasma levels displayed >4-fold elevated miR-21 levels, low superoxide dismutase 2 expression, and impaired migratory capacity, which could be normalized by miR-21 antagonism.


CONCLUSIONS
We identified a novel miR-21-dependent mechanism of ADMA-mediated APC dysfunction. MiR-21 antagonism therefore emerges as an interesting strategy to improve dysfunctional APCs in patients with coronary artery disease.
Fleissner
Felix
F
Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.
Jazbutyte
Virginija
V
Fiedler
Jan
J
Gupta
Shashi K
SK
Yin
Xiaoke
X
Xu
Qingbo
Q
Galuppo
Paolo
P
Kneitz
Susanne
S
Mayr
Manuel
M
Ertl
Georg
G
Bauersachs
Johann
J
Thum
Thomas
T
D020533:Angiogenesis Inhibitors / Q000502:physiology*; D001120:Arginine / Q000031:analogs & derivatives* / Q000502:physiology; D003324:Coronary Artery Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology
D020533:Angiogenesis Inhibitors; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C018524:N,N-dimethylarginine; D001120:Arginine