Abstract
The cellular mechanisms of primary varicose great saphenous veins (GSVs) involve inflammation, apoptosis, and proliferation of local cells and extracellular matrix degradation. Long non-coding RNAs (lncRNAs) play important roles in these cellular processes; however, which and how lncRNAs related to these mechanisms take effect on GSVs remain unclear. By screening lncRNAs that might experience changes in GSV varicosities, we selected the lower expressed lncRNA-GAS5 (growth arrest specific transcript 5) for functional assessments. Silencing of lncRNA-GAS5 promoted cell proliferation and migration, and cell cycle of the human saphenous vein smooth muscle cells (HSVSMCs), whereas overexpressing it inhibited these cellular behaviors and reduced apoptosis of HSVSMCs. RNA pull-down experiment revealed a direct bind of lncRNA-GAS5 to a Ca2+-dependent RNA-binding protein, Annexin A2. Further experiments showed that silencing of Annexin A2 reduced the HSVSMCs proliferation and vice versa. In the context of lncRNA-GAS5 knockdown, silencing of Annexin A2 reduced the proliferation of HSVSMCs while overexpression of Annexin A2 increased the proliferation. Thus, the low expression of lncRNA-GAS5 may facilitate HSVSMCs proliferation and migration through Annexin A2 and thereby the pathogenesis of GSV varicosities.
Highlights
Varicose veins, with leg edema, chronic and disabling venous ulceration, affect 25% adult population and lead to considerable morbidity and cost of health service resources, while greatPLOS ONE | DOI:10.1371/journal.pone.0120550 March 25, 2015long non-coding RNAs (lncRNAs)-GAS5 in Human Primary Varicose Great Saphenous Veins saphenous veins (GSVs) or saphenofemoral junction account for about 70% of varicose veins [1,2,3]
The migration abilities of human saphenous vein smooth muscle cells (HSVSMCs) were reflected indirectly by the new migration cells counting with Transwell
Silencing Annexin A2 followed by silencing lncRNA-GAS5 reduce HSVSMCs proliferation compared to silencing lncRNA-GAS5 only while overexpressing Annexin A2 followed by silencing lncRNA-GAS5 increase its proliferation (Fig. 7E). These findings suggest that Annexin A2 mediated lncRNA-GAS5 inhibition facilitates HSVSMCs proliferation and migration and the pathogenesis of great saphenous veins (GSVs) varicosities
Summary
With leg edema, chronic and disabling venous ulceration, affect 25% adult population and lead to considerable morbidity and cost of health service resources, while greatPLOS ONE | DOI:10.1371/journal.pone.0120550 March 25, 2015lncRNA-GAS5 in Human Primary Varicose Great Saphenous Veins saphenous veins (GSVs) or saphenofemoral junction account for about 70% of varicose veins [1,2,3]. The pathogenesis processes of GSVs are associated with leukocyte diapedesis and local inflammation, smooth muscle cell (SMC) apoptosis and proliferation, extracellular matrix degradation, and endothelial cell injury, which result in venous valvular dysfunctions that cause blood reflux, vein wall tension increase, vein wall dilation and tissue remodeling [3,4,5]. The molecular pathways involved in these processes remain elusive. We selected lncRNAs relating to cell proliferation, growth, apoptosis, tumor genesis and vascular disease in lncRNAdb database, which provides detailed lncRNA information, including sequences, functions, expressions, associated proteins and cellular locations [11], to observe which and how long non-coding RNAs (lncRNAs) take effects on the pathology of GSVs. This study helps identify novel molecular mechanisms involved in the pathogenesis of GSVs
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