Low-dose simultaneous delivery of adenovirus encoding hepatocyte growth factor and vascular endothelial growth factor in dogs enhances liver proliferation without systemic growth factor elevation

Hussein M. Atta, Ayman Al-Hendy, Salama A. Salama, Olfat G. Shaker, Olfat A. Hammam

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) gene transfer proved to enhance liver regeneration. However, elevation of their plasma levels may induce potentially serious distant effects such as tumorigenesis or proliferative retinopathy. Aims: This study was performed to examine whether simultaneous administration of low-dose adenovirus encoding HGF and VEGF genes in dogs will stimulate liver proliferation but without inducing liver toxicity or systemic elevation of HGF and VEGF levels. Methods: Adult dogs received an intravenous injection of low-dose adenoviral vectors encoding human HGF and VEGF (HGF/VEGF), β-galactosidase (lacZ) or phosphate-buffered saline (PBS). Liver proliferation was measured using the proliferating cell nuclear antigen (PCNA) immunostaining labelling index. HGF and VEGF plasma concentrations and transaminases were repeatedly measured. Transgene expression was evaluated using reverse-transcription polymerase chain reaction. Results: Human HGF and VEGF expressions were detected only in the liver of HGF/VEGF dogs at day 2 after injection but declined at sacrifice (day 7). No expression was detected in the liver of the lacZ or PBS groups. Plasma levels of HGF and VEGF were not statistically different from those in the lacZ group (P = 0.81, P = 0.22 respectively). The PCNA labelling index was five-fold higher in the HGF/VEGF group compared with the lacZ group (P < 0.01). No immunostaining was detected in the PBS group. Transaminases were only elevated (P < 0.01) in the lacZ group compared with the other groups. Conclusions: We showed that simultaneous administration of low-dose adenoviral vectors encoding human HGF and VEGF genes can induce transgene expression and liver proliferation without liver toxicity or systemic growth factor elevation.

Original languageEnglish (US)
Pages (from-to)1022-1030
Number of pages9
JournalLiver International
Volume29
Issue number7
DOIs
StatePublished - Jul 20 2009

Fingerprint

Hepatocyte Growth Factor
Adenoviridae
Vascular Endothelial Growth Factor A
Intercellular Signaling Peptides and Proteins
Dogs
Liver
Phosphates
Proliferating Cell Nuclear Antigen
Transaminases
Transgenes
Galactosidases
Genes
Liver Regeneration
Intravenous Injections
Reverse Transcription
Carcinogenesis
Polymerase Chain Reaction
Injections

Keywords

  • Adenovirus
  • Angiogenesis
  • Hepatocyte growth factor
  • Liver regeneration
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Hepatology

Cite this

Low-dose simultaneous delivery of adenovirus encoding hepatocyte growth factor and vascular endothelial growth factor in dogs enhances liver proliferation without systemic growth factor elevation. / Atta, Hussein M.; Al-Hendy, Ayman; Salama, Salama A.; Shaker, Olfat G.; Hammam, Olfat A.

In: Liver International, Vol. 29, No. 7, 20.07.2009, p. 1022-1030.

Research output: Contribution to journalArticle

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abstract = "Background: Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) gene transfer proved to enhance liver regeneration. However, elevation of their plasma levels may induce potentially serious distant effects such as tumorigenesis or proliferative retinopathy. Aims: This study was performed to examine whether simultaneous administration of low-dose adenovirus encoding HGF and VEGF genes in dogs will stimulate liver proliferation but without inducing liver toxicity or systemic elevation of HGF and VEGF levels. Methods: Adult dogs received an intravenous injection of low-dose adenoviral vectors encoding human HGF and VEGF (HGF/VEGF), β-galactosidase (lacZ) or phosphate-buffered saline (PBS). Liver proliferation was measured using the proliferating cell nuclear antigen (PCNA) immunostaining labelling index. HGF and VEGF plasma concentrations and transaminases were repeatedly measured. Transgene expression was evaluated using reverse-transcription polymerase chain reaction. Results: Human HGF and VEGF expressions were detected only in the liver of HGF/VEGF dogs at day 2 after injection but declined at sacrifice (day 7). No expression was detected in the liver of the lacZ or PBS groups. Plasma levels of HGF and VEGF were not statistically different from those in the lacZ group (P = 0.81, P = 0.22 respectively). The PCNA labelling index was five-fold higher in the HGF/VEGF group compared with the lacZ group (P < 0.01). No immunostaining was detected in the PBS group. Transaminases were only elevated (P < 0.01) in the lacZ group compared with the other groups. Conclusions: We showed that simultaneous administration of low-dose adenoviral vectors encoding human HGF and VEGF genes can induce transgene expression and liver proliferation without liver toxicity or systemic growth factor elevation.",
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T1 - Low-dose simultaneous delivery of adenovirus encoding hepatocyte growth factor and vascular endothelial growth factor in dogs enhances liver proliferation without systemic growth factor elevation

AU - Atta, Hussein M.

AU - Al-Hendy, Ayman

AU - Salama, Salama A.

AU - Shaker, Olfat G.

AU - Hammam, Olfat A.

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N2 - Background: Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) gene transfer proved to enhance liver regeneration. However, elevation of their plasma levels may induce potentially serious distant effects such as tumorigenesis or proliferative retinopathy. Aims: This study was performed to examine whether simultaneous administration of low-dose adenovirus encoding HGF and VEGF genes in dogs will stimulate liver proliferation but without inducing liver toxicity or systemic elevation of HGF and VEGF levels. Methods: Adult dogs received an intravenous injection of low-dose adenoviral vectors encoding human HGF and VEGF (HGF/VEGF), β-galactosidase (lacZ) or phosphate-buffered saline (PBS). Liver proliferation was measured using the proliferating cell nuclear antigen (PCNA) immunostaining labelling index. HGF and VEGF plasma concentrations and transaminases were repeatedly measured. Transgene expression was evaluated using reverse-transcription polymerase chain reaction. Results: Human HGF and VEGF expressions were detected only in the liver of HGF/VEGF dogs at day 2 after injection but declined at sacrifice (day 7). No expression was detected in the liver of the lacZ or PBS groups. Plasma levels of HGF and VEGF were not statistically different from those in the lacZ group (P = 0.81, P = 0.22 respectively). The PCNA labelling index was five-fold higher in the HGF/VEGF group compared with the lacZ group (P < 0.01). No immunostaining was detected in the PBS group. Transaminases were only elevated (P < 0.01) in the lacZ group compared with the other groups. Conclusions: We showed that simultaneous administration of low-dose adenoviral vectors encoding human HGF and VEGF genes can induce transgene expression and liver proliferation without liver toxicity or systemic growth factor elevation.

AB - Background: Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) gene transfer proved to enhance liver regeneration. However, elevation of their plasma levels may induce potentially serious distant effects such as tumorigenesis or proliferative retinopathy. Aims: This study was performed to examine whether simultaneous administration of low-dose adenovirus encoding HGF and VEGF genes in dogs will stimulate liver proliferation but without inducing liver toxicity or systemic elevation of HGF and VEGF levels. Methods: Adult dogs received an intravenous injection of low-dose adenoviral vectors encoding human HGF and VEGF (HGF/VEGF), β-galactosidase (lacZ) or phosphate-buffered saline (PBS). Liver proliferation was measured using the proliferating cell nuclear antigen (PCNA) immunostaining labelling index. HGF and VEGF plasma concentrations and transaminases were repeatedly measured. Transgene expression was evaluated using reverse-transcription polymerase chain reaction. Results: Human HGF and VEGF expressions were detected only in the liver of HGF/VEGF dogs at day 2 after injection but declined at sacrifice (day 7). No expression was detected in the liver of the lacZ or PBS groups. Plasma levels of HGF and VEGF were not statistically different from those in the lacZ group (P = 0.81, P = 0.22 respectively). The PCNA labelling index was five-fold higher in the HGF/VEGF group compared with the lacZ group (P < 0.01). No immunostaining was detected in the PBS group. Transaminases were only elevated (P < 0.01) in the lacZ group compared with the other groups. Conclusions: We showed that simultaneous administration of low-dose adenoviral vectors encoding human HGF and VEGF genes can induce transgene expression and liver proliferation without liver toxicity or systemic growth factor elevation.

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KW - Angiogenesis

KW - Hepatocyte growth factor

KW - Liver regeneration

KW - Vascular endothelial growth factor

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