Abstract
The activation of endothelial cells is essential to repair damage caused by atherosclerosis via endothelial cell proliferation and migration. Overexpression of VEGF (vascular endothelial growth factor) and the downstream gene, B-cell lymphoma-2 (BCL-2) could result in apoptosis-resistant endothelial cells, which are responsible for aggravated hyperplasia and instable plaques generation. Previous studies have shown that miRNA126 could regulate the expression of VEGF. Here, we verified the existence of a miRNA126 binding site in VEGF’s 3’UTR. Additionally, VEGF regulated BCL-2 expression via AP1 (Activator Protein 1) binding site in BCL-2’s promoter. Next, we established an apoptosis-resistant endothelial cell line and constructed a lentiviral vector to express miRNA126 under the control of the BCL-2 promoter to investigate whether conditional expression of miRNA126 could modulate VEGF and BCL-2 expression in apoptosis-resistant endothelial cells. This lentiviral system specifically expressed miRNA126 in cells with high BCL-2 levels, downregulated VEGF expression, inhibited MAPK pathway activation and downregulated BCL-2 expression via suppression of AP1, and as a whole, reduced apoptosis-resistant endothelial cells, while the effects of miRNA126 on normal endothelial cells were relatively small. Our results demonstrate that conditional miRNA126 overexpression under the control of the downstream BCL-2 promoter provides a flexible regulatory strategy for reducing the apoptosis-resistant endothelial cells without having a significant impact on normal endothelial cells.
Highlights
Atherosclerosis, the most common vascular disease caused by arterial sclerosis, develops from an accumulation of lipids and complex carbohydrates on vascular walls, could result in hemorrhaging, thrombogenesis, proliferation of fibrous tissue, calcium deposition, and the gradual decay and calcification of the atrial wall medial layer[1]
The major findings of present study are as follows: 1. There is a negative correlation between expressions of miRNA126 and VEGF and B-cell lymphoma-2 (BCL-2) in ox-LDL induced apoptosis-resistant endothelial cells
Conditional miRNA126 overexpression could downregulate VEGF and BCL-2 expression and reduce the resistance to apoptosis in apoptosis-resistant endothelial cells and these effects are partly mediated through AP1
Summary
Atherosclerosis, the most common vascular disease caused by arterial sclerosis, develops from an accumulation of lipids and complex carbohydrates on vascular walls, could result in hemorrhaging, thrombogenesis, proliferation of fibrous tissue, calcium deposition, and the gradual decay and calcification of the atrial wall medial layer[1]. According to vascular endothelial injury and repair theory, new endothelial cells, mainly originating from proliferating vessel endothelial cells and from blood endothelial progenitor cells at the plaque lesions, could fill in the damaged regions to resist apoptosis of endothelial cells [5]. It is reported that, during the repair of a vascular injury, endothelial cells express and secrete high levels of VEGF and BCL-2, which could accelerate the differentiation of endothelial progenitor cells into endothelial cells [7] These endothelial cells lost the ability to repair themselves through spontaneous apoptosis and proliferation under normal conditions and are resistant to apoptosis, forming so called apoptosis-resistant endothelial cells, which are responsible for aggravated hyperplasia and instable plaques generation[8]. Selective inhibition of apoptosis-resistant endothelial cells may be a favorable strategy for treating atherosclerosis, while non-selective inhibition on endothelial cells may directly or indirectly increase the shedding of the vascular endothelial cells and aggravate atherosclerosis [9,10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
