Abstract
Endothelial barrier integrity is essential for vascular homeostasis and increased vascular permeability and has been implicated in many pathological processes, including diabetic retinopathy. Here, we investigated the effect of Rk1, a ginsenoside extracted from sun ginseng, on regulation of endothelial barrier function. In human retinal endothelial cells, Rk1 strongly inhibited permeability induced by VEGF, advanced glycation end-product, thrombin, or histamine. Furthermore, Rk1 significantly reduced the vessel leakiness of retina in a diabetic mouse model. This anti-permeability activity of Rk1 is correlated with enhanced stability and positioning of tight junction proteins at the boundary between cells. Signaling experiments revealed that Rk1 induces phosphorylation of myosin light chain and cortactin, which are critical regulators for the formation of the cortical actin ring structure and endothelial barrier. These findings raise the possibility that ginsenoside Rk1 could be exploited as a novel prototype compound for the prevention of human diseases that are characterized by vascular leakage.
Highlights
The disruption of endothelial barrier integrity leading to increased vasopermeability contributes to many pathological processes, including various inflammatory diseases, acute lung injury, and diabetic retinopathy [1,2]
Our preliminary results showed that Rk1, a major component of SG135, which is a mixture of ginsenosides extracted from sun ginseng, has a profound effect on the viability of human retina endothelial cells (HRECs) as compared to other derivatives of ginsenosides
To address whether or not the inhibitory effect of Rk1 on VEGF-induced vasopermeability is due to changes in the levels of tight junctions (TJs) protein expression, we examined the transcription levels of a subset of representative TJ proteins (ZO-1, zonula occludins (ZO)-2, and occludin)
Summary
The disruption of endothelial barrier integrity leading to increased vasopermeability contributes to many pathological processes, including various inflammatory diseases, acute lung injury, and diabetic retinopathy [1,2]. Endothelial permeability is tightly controlled by cell-cell junctions, including adherent junctions (AJs) and tight junctions (TJs), between neighboring endothelial cells [3,4]. TJs consist of a number of proteins, including occludin, claudins, junctional adhesion molecules (JAMs), and zonula occludins (ZO). Claudins, and JAMs are major integral transmembrane proteins with adhesive properties, and are believed to be responsible for the formation of a tight seal between two apposing endothelial membranes of adjacent cells [3]. Occludin and claudins form homodimeric bridges, and ZOs connect these integral transmembrane proteins to actin filaments [5,6,7]. Dynamic regulation of perijunctional actin has been suggested to control paracellular permeability by affecting the stability of TJs closely connected to the actin cytoskeleton, either directly or indirectly [8,9]. Actin is likely to play a critical role in modulating the integrity of TJs, and endothelial permeability
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