Ritonavir inhibits HIF-1α-mediated VEGF expression in retinal pigment epithelial cells in vitro

Vadlapatla, Ramya Krishna; Vadlapudi, Aswani Dutt; Pal, Dhananjay; Mukherji, Mridul; Mitra, Ashim K.

doi:10.1038/eye.2013.240

Cited by 37 publications

(26 citation statements)

References 40 publications

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“…HIF-1α levels are subject to complex translational controls operating through nutrient and cellular energy-sensing mTOR complexes [28], and VEGF production is partially dependent on mTORC1-induced HIF-1α expression [29]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

Ding

Shan

Nai

et al. 2018

Cell Physiol Biochem

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Background/Aims: The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway In vitro experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis in vivo is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms. Methods: Cre/loxP conditional gene knockout strategy was used to delete the Deptor gene in mouse vascular ECs. The expression or distribution of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) were detected by immunohistochemical staining or western blot. Tube formation assay was used to measure angiogenesis in vitro. Results: Deptor knockdown led to increased expression of CD31, VEGF and HIF-1α in heart, liver, kidney and aorta. After treatment with rapamycin, their expression was significantly down regulated. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with DEPTOR-specific small interfering RNA (siRNA), which resulted in a significant increase in endothelial tube formation and migration rates. In contrast, DEPTOR overexpression markedly reduced the expression of CD31, VEGF and HIF-1α. Conclusions: Our findings demonstrated that deletion of the Deptor gene in vascular ECs resulted in upregulated expression of CD31 and HIF-1α, and further stimulated the expression of VEGF which promoted angiogenesis, indicating that disruption of normal angiogenic pathways may occur through hyperactivation of the mTORC1/HIF-1α/VEGF signaling pathway.

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Section: Resultsmentioning

confidence: 99%

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

Ding

Shan

Nai

et al. 2018

Cell Physiol Biochem

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“…Hypoxia occurs secondary to a number of disease processes in the human body (9). In response to hypoxia, retinal pigment epithelial cells (RPE cells) rapidly release various growth factors resulting in angiogenesis, fibrovascular tissue formation and retinal ablation (10). Among the hypoxia-stimulated growth factors, vascular endothelial growth factor (VEGF), a potent vascular endothelial cell mitogen, is a pivotal regulator of vasculogenesis and angiogenesis in CNV (11).…”

Section: Introductionmentioning

confidence: 99%

Caffeic acid phenethyl ester reduces the secretion of vascular endothelial growth factor through the inhibition of the ROS, PI3K and HIF-1α signaling pathways in human retinal pigment epithelial cells under hypoxic conditions

Paeng

Jung

Park

et al. 2015

International Journal of Molecular Medicine

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Choroidal neovascularization (CNV) can lead to progressive and severe visual loss. Vascular endothelial growth factor (VEGF) promotes the development of CNV. Caffeic acid phenethyl ester (CAPE), a biologically active component of the honeybee (Apis mellifera) propolis, has been demonstrated to have several interesting biological regulatory properties. The objective of this study was to determine whether treatment with CAPE results in the inhibition of the production of vascular endothelial growth factor (VEGF) in retinal pigment epithelial cells (RPE cells) under hypoxic conditions and to explore the possible underlying mechanisms. An in vitro experimental model of hypoxia was used to mimic an ischemic microenvironment for the RPE cells. Human RPE cells (ARPE-19) were exposed to hypoxia with or without CAPE pre-treatment. ARPE-19 cells were used to investigate the pathway involved in the regulation of VEGF production under hypoxic conditions, based on western blot analysis, enzyme-linked immunosorbent assay (ELISA) and electrophoretic mobility shift assay (EMSA). The amount of VEGF released from the hypoxia-exposed cells was significantly higher than that of the normoxic controls. Pre-treatment with CAPE suppressed the hypoxia-induced production of VEGF in the ARPE-19 cells, and this effect was inhibited through the attenuation of reactive oxygen species (ROS) production, and the inhibition of phosphoinositide 3-kinase (PI3K)/AKT and hypoxia-inducible factor-1α (HIF-1α) expression. These in vitro findings suggest that CAPE may prove to be a novel anti-angiogenic agent for the treatment of diseases associated with CNV.

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“…Aside from the previously mentioned angiogenic inhibitors, a variety of alternative mechanisms of action and gene transfer therapies are currently under investigation, such as targeting vascular endothelial receptor tyrosine kinase [37], overexpressed integrins [38], hypoxia-induced activator [39] or metalloproteinases [40], among others [41]. Notwithstanding the potential of these strategies, only preliminary studies have been conducted and the possible adverse effects on normal choroidal vessels and retinal neurons remain to be evaluated [27,42].…”

Section: Drug Delivery To the Posteriors Segment Of The Eyementioning

confidence: 98%

Delivery strategies for treatment of age-related ocular diseases: From a biological understanding to biomaterial solutions

Delplace

Payne

Shoichet

2015

Journal of Controlled Release

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Ritonavir inhibits HIF-1α-mediated VEGF expression in retinal pigment epithelial cells in vitro

Abstract: Purpose Retinal hypoxia-mediated activation of the hypoxia-inducible factor (HIF pathway) leading to angiogenesis is a major signaling mechanism underlying a number of sight-threatening diseases.

Cited by 37 publications

References 40 publications

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

Caffeic acid phenethyl ester reduces the secretion of vascular endothelial growth factor through the inhibition of the ROS, PI3K and HIF-1α signaling pathways in human retinal pigment epithelial cells under hypoxic conditions

Delivery strategies for treatment of age-related ocular diseases: From a biological understanding to biomaterial solutions

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