Abstract 20452: Microrna-200b Induces Endothelial Progenitor Cell Apoptosis and Senescence by Targeting Cjun Expression
Introduction: Lineage negative bone marrow cells (Lin-BMCs) mediate vascular repair. Aging-associated apoptosis and senescence result in reduced number and impair Lin-BMCs’s pro-repair capacity. Molecular mechanisms underlying lin-BMCs apoptosis and senescence remain poorly understood. MicroRNAs (miRNAs) regulate many important biological processes. The identification of miRNA-mRNA networks that modulate the health and functionality of lin- BMCs is a critical step in understanding the process of vascular repair.
Hypothesis: miR-200b-cJun network plays a vital role in regulating Lin- BMCs apoptosis, senescence and self renewal in angiogenesis.
Methods: Lin- BMCs were isolated from young (3-week-old) wild type (WT), young apoE-/- , aged WT (29-month-old) and aged apoE-/- (12 month-old) C57BL/6 mice. Global miRNA and gene expression profiling were analyzed.
Results: Transcriptome analysis in Lin- BMCs isolated from young and aged WT and apoE-/- mice showed a significant aging-associated increase in miR-200b expression. We found that C-Jun was predicted to be a miR-200b target and c-Jun expression was reversely correlated with miR-200b levels. Luciferase reporter assays confirmed c-Jun as a direct target of miR-200b. MiR-200b overexpression in young lin-BMCs inhibited c-Jun expression, resulting in increased senescence and apoptosis in vitro and impaired angiogenic capacity in vivo. In contrast, suppression of miR-200b or overexpression of c-Jun in aged lin-BMCs increased c-Jun expression rejuvenated Lin-BMCs with decreased senescence and apoptosis, leading to improved angiogenesis in vitro and in vivo.
Conclusions: Using genomic and functional studies, we discovered that miR-200b regulates apoptosis and senescence of age-associated lin-BMCs by suppressing c-Jun expression, thus negatively affecting vascular repair capacity of those cells in atherogenesis. Modulation of miR-200b and/or its target c-Jun may suggest a potential therapeutic intervention to improve Lin-BMCs-mediated angiogenesis and vascular repair.
Author Disclosures: S. Zhu: None. S. Deng: None. C. Jia: None. Q. Ma: None. E. Chen: None. W. Zhu: None. P.J. Goldschmidt-Clermont: None. C. Dong: None.
- © 2014 by American Heart Association, Inc.