Abstract 20452: Microrna-200b Induces Endothelial Progenitor Cell Apoptosis and Senescence by Targeting Cjun Expression

Abstract

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.