MicroRNA-10A* and MicroRNA-21 Modulate Endothelial Progenitor Cell Senescence Via Suppressing High-Mobility Group A2

Abstract

Rationale Endothelial progenitor cells (EPCs) contribute to the regeneration of endothelium. Aging-associated senescence results in reduced number and function of EPCs, potentially contributing to increased cardiac risk, reduced angiogenic capacity, and impaired cardiac repair effectiveness. The mechanisms underlying EPC senescence are unknown. Increasing evidence supports the role of microRNAs in regulating cellular senescence. Objective We aimed to determine whether microRNAs regulated EPC senescence and, if so, what the underlying mechanisms are. Methods and Results To map the microRNA/gene expression signatures of EPC senescence, we performed microRNA profiling and microarray analysis in lineage-negative bone marrow cells from young and aged wild-type and apolipoprotein E–deficient mice. We identified 2 microRNAs, microRNA-10A* (miR-10A*), and miR-21, and their common target gene Hmga2 as critical regulators for EPC senescence. Overexpression of miR-10A* and miR-21 in young EPCs suppressed Hmga2 expression, caused EPC senescence, as evidenced by senescence-associated β–galactosidase upregulation, decreased self-renewal potential, increased p16Ink4a/p19Arf expression, and resulted in impaired EPC angiogenesis in vitro and in vivo, resembling EPCs derived from aged mice. In contrast, suppression of miR-10A* and miR-21 in aged EPCs increased Hmga2 expression, rejuvenated EPCs, resulting in decreased senescence-associated β–galactosidase expression, increased self-renewal potential, decreased p16Ink4a/p19Arf expression, and improved EPC angiogenesis in vitro and in vivo. Importantly, these phenotypic changes were rescued by miRNA-resistant Hmga2 cDNA overexpression. Conclusions miR-10A* and miR-21 regulate EPC senescence via suppressing Hmga2 expression and modulation of microRNAs may represent a potential therapeutic intervention in improving EPC-mediated angiogenesis and vascular repair.

let-7 Contributes to Diabetic Retinopathy but Represses Pathological Ocular Angiogenesis

“…The HMGA2 gene is an established key let-7 target gene in several different cell types (44)(45)(46). Consistent with our results in EC cells, HMGA2 has been shown to be required and sufficient to modulate proliferation, migration, and angiogenesis in endothelial progenitor cells (EPCs) in vitro and the angiogenic capability of bone marrow cells (BMCs) in vivo (51). In an independent study, knockdown of let-7f was shown to repress angiogenesis in a spheroid sprouting assay, suggesting that let-7f may promote angiogenesis (42).…”

Age‐associated downregulation of vasohibin‐1 in vascular endothelial cells

“…It is estimated that approximately one‐third of all animal genes are controlled by microRNAs, and thus, microRNAs exhibit a wide range of biological processes including aging (Breving & Esquela‐Kerscher, 2010). Indeed, several earlier studies were directed to examine the relationship between microRNAs and endothelial cell senescence (Menghini et al ., 2009; Zhao et al ., 2010; Jong et al ., 2013; Olivieri et al ., 2013; Zhu et al ., 2013). Our present comprehensive microarray analysis revealed that the microRNA with the third highest augmented expression in senescent HUVECs was miR‐22‐3p and that it had a binding site on the 3′ UTR of VASH1 mRNA.…”

Expression of microRNA-10a, microRNA-342-3p and their predicted target gene TIAM1 in extranodal NK/T-cell lymphoma, nasal type

“…Previous studies have identified several target genes of miR-10a, including high-mobility group A2 (26), cell adhesion molecule L1-like (27), homeobox (HOX)A1 (28) and HOXD4 (29), which are involved in cellular differentiation, growth, migration and invasion in various pathophysiological processes (26)(27)(28)(29). Other studies have demonstrated that the expression of miR-342-3p is downregulated in the blood and tumor tissues of patients with cancer, including colorectal cancer (30), clinical glioblastoma multiforme (31), breast tumor (32), acute lymphoblastic leukemia (33) and Sézary syndrome (34).…”