Platelet-derived growth factor B chain is a novel target gene of cocaine-mediated Notch1 signaling: Implications for HIV-associated neurological disorders

Honghong Yao, Ming Duan, Guoku Hu, Shilpa J Buch

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Abstract

Neuroinflammation associated with HIV-1 infection is exacerbated in cocaine-abusing, HIV+individuals. The underlying mechanisms are, in part, attributable to disruption of the blood- brain barrier modulated by cocaine via platelet-derived growth factor B chain (PDGF-B). Since Notch signaling plays a critical role in CNS homeostasis, we hypothesized that it may have a role in cocaine-mediated induction of PDGF-B. The goal of this study was to link Notch signaling with PDGF-B. Using Western blot analysis, we demonstrate the role of Notch1 signaling in cocaine-mediated induction of PDGF-B in human brain microvascular endothelial cells. Exposure of cells to the γ-secretase inhibitor-DAPT or silencing of Notch1 resulted in abrogation of cocaine-mediated induction of PDGF-B. Reciprocally, activation of the Notch1 receptor by exposing cells to the Notch ligand Jagged-1 resulted in upregulation of PDGF-B expression. Furthermore, it was demonstrated that cocaine-mediated activation of Notch1 signaling leading to targeted expression of PDGF-B involved activation of the downstream effector CSL. Functional implication of Notch1 signaling in regulating expression of the vascular permeant PDGF-B was confirmed in vitro using cell permeability assays. In vivo relevance was further corroborated in cocaine-treated mice that demonstrated increased permeability of the endothelial barrier as evidenced by Evans blue and sodium fluorescein extravasation. Specificity of Notch1 signaling in vivo was validated in mice exposed to DAPT, which failed to demonstrate barrier disruption following cocaine exposure. This is the first evidence of involvement of Notch1 activation in cocaine-mediated regulation of PDGF-B expression.

Original languageEnglish (US)
Pages (from-to)12449-12454
Number of pages6
JournalJournal of Neuroscience
Volume31
Issue number35
DOIs
StatePublished - Aug 31 2011

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Proto-Oncogene Proteins c-sis
Nervous System Diseases
Cocaine
HIV
Genes
Permeability
Notch1 Receptor
Amyloid Precursor Protein Secretases
Evans Blue
Blood-Brain Barrier
Fluorescein
HIV Infections
Blood Vessels
HIV-1
Homeostasis
Up-Regulation
Endothelial Cells
Western Blotting
Ligands

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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title = "Platelet-derived growth factor B chain is a novel target gene of cocaine-mediated Notch1 signaling: Implications for HIV-associated neurological disorders",
abstract = "Neuroinflammation associated with HIV-1 infection is exacerbated in cocaine-abusing, HIV+individuals. The underlying mechanisms are, in part, attributable to disruption of the blood- brain barrier modulated by cocaine via platelet-derived growth factor B chain (PDGF-B). Since Notch signaling plays a critical role in CNS homeostasis, we hypothesized that it may have a role in cocaine-mediated induction of PDGF-B. The goal of this study was to link Notch signaling with PDGF-B. Using Western blot analysis, we demonstrate the role of Notch1 signaling in cocaine-mediated induction of PDGF-B in human brain microvascular endothelial cells. Exposure of cells to the γ-secretase inhibitor-DAPT or silencing of Notch1 resulted in abrogation of cocaine-mediated induction of PDGF-B. Reciprocally, activation of the Notch1 receptor by exposing cells to the Notch ligand Jagged-1 resulted in upregulation of PDGF-B expression. Furthermore, it was demonstrated that cocaine-mediated activation of Notch1 signaling leading to targeted expression of PDGF-B involved activation of the downstream effector CSL. Functional implication of Notch1 signaling in regulating expression of the vascular permeant PDGF-B was confirmed in vitro using cell permeability assays. In vivo relevance was further corroborated in cocaine-treated mice that demonstrated increased permeability of the endothelial barrier as evidenced by Evans blue and sodium fluorescein extravasation. Specificity of Notch1 signaling in vivo was validated in mice exposed to DAPT, which failed to demonstrate barrier disruption following cocaine exposure. This is the first evidence of involvement of Notch1 activation in cocaine-mediated regulation of PDGF-B expression.",
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AU - Buch, Shilpa J

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