Micro-RNA-34a contributes to the impaired function of bone marrow-derived mononuclear cells from patients with cardiovascular disease.
OBJECTIVE
This study evaluated the regulation and function of micro-RNAs (miRs) in bone marrow-mononuclear cells (BMCs).


BACKGROUND
Although cell therapy with BMCs may represent a therapeutic option to treat patients with heart disease, the impaired functionality of patient-derived cells remains a major challenge. Small noncoding miRs post-transcriptionally control gene expression patterns and play crucial roles in modulating cell survival and function.


METHODS
Micro-RNAs were detected by miR profiling in BMCs isolated from healthy volunteers (n = 6) or from patients with myocardial infarction (n = 6), and the results were confirmed by polymerase chain reaction (PCR) in a larger cohort (n = 37). The function of selected miRs was determined by gain-of-function studies in vitro and by locked nuclear acid (LNA) modified inhibitors in vitro and in vivo.


RESULTS
We identified several miRs that are up-regulated in BMCs from patients with myocardial infarction compared with BMCs from healthy controls, including the pro-apoptotic and antiproliferative miR-34a and the hypoxia-controlled miR-210. Inhibition of miR-34 by LNA-34a significantly reduced miR-34a expression and blocked hydrogen peroxide-induced cell death of BMC in vitro, whereas overexpression of miR-34a reduced the survival of BMCs in vitro. Pre-treatment of BMCs with LNA-34a ex vivo significantly increased the therapeutic benefit of transplanted BMCs in mice after acute myocardial infarction (AMI).


CONCLUSIONS
These results demonstrate that cardiovascular disease modulates the miR expression of BMCs in humans. Reducing the expression of the pro-apoptotic miR-34a improves the survival of BMCs in vitro and enhances the therapeutic benefit of cell therapy in mice after AMI.
Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, Frankfurt, Germany.
Quanfu
Q
Xu
Florian H
FH
Seeger
Jessica
J
Castillo
Kazuma
K
Iekushi
Reinier A
RA
Boon
Ruxandra
R
Farcas
Yosif
Y
Manavski
Yi-Gang
YG
Li
Birgit
B
Assmus
Andreas M
AM
Zeiher
Stefanie
S
Dimmeler
D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology* / Q000502:physiology; D016026:Bone Marrow Transplantation / Q000379:methods; D002318:Cardiovascular Diseases / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D016022:Case-Control Studies; D002470:Cell Survival / Q000235:genetics*; D002478:Cells, Cultured; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D016133:Polymerase Chain Reaction / Q000379:methods; D012016:Reference Values
C522425:MIRN34 microRNA, human; D035683:MicroRNAs