Silencing p75NTR prevents proNGF-induced endothelial cell death and development of acellular capillaries in rat retina

Ahmed Y. Shanab, Barbara A. Mysona, Suraporn Matragoon, Azza B. El-Remessy

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Accumulation of the nerve growth factor precursor (proNGF) and its receptor p75NTR have been associated with several neurodegenerative diseases in both brain and retina. However, whether proNGF contributes to microvascular degeneration remain unexplored. This study seeks to investigate the mechanism by which proNGF/p75NTR induce endothelial cell (EC) death and development of acellular capillaries, a surrogate marker of retinal ischemia. Stable overexpression of the cleavage-resistant proNGF and molecular silencing of p75NTR were utilized in human retinal EC and rat retinas in vivo. Stable overexpression of proNGF decreased NGF levels and induced retinal vascular cell death evident by 1.9-fold increase in acellular capillaries and activation of JNK and cleaved-PARP that were mitigated by p75NTRshRNA. In vitro, overexpression of proNGF did not alter TNF-α level, reduced NGF, however induced EC apoptosis evident by activation of JNK and p38 MAPK, cleaved-PARP. Silencing p75NTR using siRNA restored expression of NGF and TrkA activation and prevented EC apoptosis. Treatment of EC with human-mutant proNGF induced apoptosis that coincided with marked protein interaction and nuclear translocation of p75NTR and the neurotrophin receptor interacting factor. These effects were abolished by a selective p75NTR antagonist. Therefore, targeting p75NTR represents a potential therapeutic strategy for diseases associated with aberrant expression of proNGF.

Original languageEnglish (US)
Number of pages1
JournalMolecular Therapy - Methods and Clinical Development
Volume2
DOIs
StatePublished - Apr 29 2015

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Retina
Nerve Growth Factor
Cell Death
Endothelial Cells
Apoptosis
Nerve Growth Factor Receptors
Retinal Vessels
p38 Mitogen-Activated Protein Kinases
Nuclear Proteins
Neurodegenerative Diseases
Small Interfering RNA
Ischemia
Biomarkers
Brain
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Silencing p75NTR prevents proNGF-induced endothelial cell death and development of acellular capillaries in rat retina. / Shanab, Ahmed Y.; Mysona, Barbara A.; Matragoon, Suraporn; El-Remessy, Azza B.

In: Molecular Therapy - Methods and Clinical Development, Vol. 2, 29.04.2015.

Research output: Contribution to journalArticle

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