Ginsenoside-Rb1-Mediated Anti-angiogenesis via Regulating PEDF and miR-33a through the Activation of PPAR-γ Pathway

Abstract

Angiogenesis is the formation of new blood vessels from the existing vasculature, which is involved in multiple biological processes, including atherosclerosis, ischemic heart disease, and cancer. Ginsenoside-Rb1 (Rb1), the most abundant ginsenoside isolated form Panax ginseng, has been identified as a promising anti-angiogenic agent via the up-regulation of PEDF. However, the underlying molecular mechanisms still unknown. In the present study, human umbilical vein endothelial cells (HUVECs) were selected to perform in vitro assays. Rb1 (0–20 nM) treatment induced pigment epithelial-derived factor (PEDF) protein expression in concentration and time-dependent manners. Interestingly, it was also demonstrated that the exposure of Rb1 (10 nM) could increase PEDF protein expression without any alteration on mRNA level, suggesting the involvement of posttranscriptional regulation. Furthermore, bioinformatics predictions indicated the regulation of miR-33a on PEDF mRNA 3′-UTR, which was further confirmed by luciferase reporter gene assay and real-time PCR. Over-expression of pre-miR-33a was found to regress partly Rb1-mediated PEDF increment and anti-angiogenic effect in HUVECs. Additionally, Rb1-reduced miR-33a and increased PEDF expression was prevented by pre-incubation with peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist (GW9662) or transfection with PPAR-γ siRNA in HUVECs. Taken together, our findings demonstrated that Rb1 exerted anti-angiogenic effects through PPAR-γ signaling pathway via modulating miR-33a and PEDF expressions. Thus, Rb1 may have the potential of being developed as an anti-angiogenic agent, however, further appropriate studies are warranted to evaluate the effect in vivo.

Ginsenoside Rb1 ameliorates CKD‐associated vascular calcification by inhibiting the Wnt/β‐catenin pathway

“…Studies have implied that ginsenosides function through nuclear receptors . Our previous study also suggests that ginsenoside Rb1 activates PPAR‐γ in HUVECs . Interestingly, new metabolites of Rb1 by microbial transformation have been reported to activate the Wnt/β‐catenin pathway, which mediates the induction of osteogenic differentiation in MC3T3‐E1 cells .…”

“…In view of the demonstration that Rb1 acts as a PPAR‐γ agonist in human umbilical vein endothelial cells (HUVECs) by our previous study, we hypothesized that ginsenoside Rb1 may protect VC through the PPAR‐γ/β‐catenin axis. To test our hypothesis, we established a CKD rat model and a VSMC calcification model to mimic clinical CKD‐associated VC in vivo and in vitro.…”

Ренопротекторний Ефект Метформіну В Щурів Із Цукровим Діабетом 2-Го Типу Реалізується Шляхом Посилення Експресії Фактора Пігментного Епітелію В Тканині Нирок

“…Many studies have demonstrated that activating PPAR-γ signaling pathway played pivotal role in PEDF's beneficial effects [25][26][27][28][29]. PPAR-γ knockdown could reduce PEDF expression [30]. The decrease of PEDF was significantly down-regulated and the increase of NF-κB and MMP-9 was down-regulated by systemically administration of PPAR-γ agonist [31].…”

“…All of the beneficial effects of PEDF on AGE-exposed podocytes were blocked by the treatment of GW9662, an inhibitor of PPAR-γ [32]. PEDF increment on human endothelial cells was blocked by the preincubation with GW9662, which resulted in the promotion of angiogenesis [30]. Moreover, it had been suggested that PEDF could interact with PPAR-γ for the regulation of angiogenesis and lipid metabolism in hepatocellular carcinoma [33], and it is necessary for protective roles of PEDF in OGD cardiomyocytes [34].…”

Asperosaponin VI inhibits LPS-induced inflammatory response by activating PPAR-γ pathway in primary microglia

“…have a good inhibitory effect on microglia-mediated neuroinflammation, which could promote the expression of anti-inflammatory cytokines by activating PPAR-γ signaling pathways (Lu et al, 2017, Zhang et al, 2018a.…”