Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Jun 18;8(3):453-8.
doi: 10.3980/j.issn.2222-3959.2015.03.04. eCollection 2015.

Anthrax lethal toxin suppresses high glucose induced VEGF over secretion through a post-translational mechanism

Wei-Wei Zhang  1 , Xin Wang  2 , Ping Xie  1 , Song-Tao Yuan  1 , Qing-Huai Liu  1
Affiliations

Anthrax lethal toxin suppresses high glucose induced VEGF over secretion through a post-translational mechanism

Wei-Wei Zhang et al. Int J Ophthalmol. .

Abstract

Aim: To prove anthrax lethal toxin (LeTx) blocks the mitogen activated protein kinases (MAPKs) activation by degrading the MAPK/ERK kinases (MEKs) to suppress vascular endothelial growth factor (VEGF) secretion.

Methods: Human adult retinal pigmented epithelium (ARPE) cells were cultured and treated with normal glucose, high glucose or high glucose with LeTx for additional 24, 48 or 72h for viable cell count. Total RNA from the ARPE was isolated for reverse transcription polymerase chain reaction (RT-PCR). The conditioned medium of ARPE cells treated in different group for 48h was filtered and diluted to detect the concentration of VEGF by enzyme-linked immunosorbant assays. Evaluate the role of MEK/MAPK pathway in the secretion of VEGF by immunoblotting.

Results: In this study, we proved high glucose induced activation of the MAPK extracellular signal-regulated kinase (ERK1/2) and p38 in the ARPE cell line was blocked by anthrax LeTx. LeTx also inhibited high glucose induced ARPE cell over proliferation.

Conclusion: LeTx suppressed high glucose induced VEGF over secretion in the ARPE cells, mainly through a post-translational mechanism.

Keywords: angiogenesis; anthrax lethal toxin; diabetic retinopathy; retinal pigmented epithelium; vascular endothelial growth factor.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Over activated MKK/MAPK pathway in the ARPE cultured in high glucose was blocked by LeTx
Immunoblotting of lysate of ARPE cells from different groups shows high glucose induced MAPK ERK1/2 and p38 over activation, this effect was blocked by LeTx by cleaving the MKK. N: 5.6 mmol/L glucose (normal glucose, N); H: 30 mmol/L glucose (high glucose, H); L: 100 ng/mL LF with 1 µg/mL PA in 30 mmol/L glucose.
Figure 2
Figure 2. LeTx prevented high glucose induced ARPE cell over proliferation
Results are expressed as a percentage of the proliferation of control cells. The high glucose promoted the ARPE cells proliferation after 48 and 72h' incubation, whereas the 100 ng/mL LF with 1 µg/mL PA (L) slightly inhibited the over proliferation of ARPE cells. 1: vs high glucose, P<0.05; 2: vs nomral glucose, P<0.05.
Figure 3
Figure 3. LeTx slightly decreased high glucose enhanced VEGF expression in ARPE cells without statistical significance
VEGF mRNA over expression under high glucose was slightly inhibited by 100 ng/mL LF with 1 µg/mL PA without significance; 2: vs normal glucose, P<0.05.
Figure 4
Figure 4. LeTx decreased VEGF concentration in the conditioned medium of ARPE cells upon high glucose stimulation through a post-translational mechanism
A: LeTx decreased VEGF concentration in the conditioned medium of ARPE cells under high glucose. 1: vs high glucose, P<0.05; 2: vs normal glucose, P<0.05. B: LeTx sequestered over expressed VEGF inside ARPE cells under high glucose condition. N: 5.6 mmol/L glucose (normal glucose, N); H: 30 mmol/L glucose (high glucose, H); L: 100 ng/mL LF with 1 µg/mL PA in 30 mmol/L glucose.
See this image and copyright information in PMC

References

    1. Simó R, Hernández C. Advances in the medical treatment of diabetic retinopathy. Diabetes Care. 2009;32(8):1556–1562. - PMC - PubMed
    1. Singleton JR, Smith AG, Russell JW, Feldman EL. Microvascular complications of impaired glucose tolerance. Diabetes. 2003;52(12):2867–2873. - PubMed
    1. Tong Z, Yang Z, Patel S, et al. Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. Proc Natl Acad Sci U S A. 2008;105(19):6998–7003. - PMC - PubMed
    1. Sodhi A, Montaner S, Patel V, Zohar M, Bais C, Mesri EA, Gutkind JS. The Kaposi's sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1alpha. Cancer Res. 2000;60(17):4873–4880. - PubMed
    1. Dalkas GA, Papakyriakou A, Vlamis-Gardikas A, Spyroulias GA. Low molecular weight inhibitors of the protease anthrax lethal factor. Mini Rev Med Chem. 2008;8(3):290–306. - PubMed

LinkOut - more resources