Phosphatidylinositol 3-kinase pathway regulates hypoxia-inducible factor-1 to protect from intestinal injury during necrotizing enterocolitis

Naira Baregamian, Piotr G. Rychahou, Hal K. Hawkins, B. Mark Evers, Dai H. Chung

Research output: Contribution to journalArticle

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Abstract

Background: Hypoxia is an important risk factor for development of necrotizing enterocolitis (NEC) in premature infants. Hypoxia-inducible factor (HIF)-1 is a transcription factor that plays a critical role in cellular responses to hypoxia and can be induced by phosphatidylinositol 3-kinase (PI3-K) pathway. Activation of the PI3-K and regulation of HIF-1 during NEC have not been elucidated. Methods: NEC was induced in 3-day-old neonatal mice using hypoxia and artificial formula feedings. Mice were divided into 3 treatment groups: (1) NEC alone, (2) NEC with insulin-like growth factor (IGF)-I, or (3) NEC with Akt1 siRNA treatment. Animals were sacrificed, and intestinal sections were harvested for protein analysis, H&E, and immunohistochemical staining. Results: In vivo model of NEC produced intestinal injury associated with increased protein expression of HIF-1α, pAkt, PARP, and caspase-3 cleavage. Pretreatment with IGF-1 attenuated an HIF-1α response. In contrast, targeted inhibition of Akt1 completely abolished NEC-induced expression of pAkt and upregulated HIF-1α activation. Conclusions: NEC activates important protective cellular responses to hypoxic injury such as HIF-1α and PI3-K/Akt in neonatal gut. Hypoxia-mediated activation of pro-survival signaling during NEC may be modulated with growth factors, which thus suggests a potential therapeutic option in the treatment of neonates with NEC.

Original languageEnglish (US)
Pages (from-to)295-302
Number of pages8
JournalSurgery
Volume142
Issue number2
DOIs
StatePublished - Aug 2007

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Phosphatidylinositol 3-Kinase
Hypoxia-Inducible Factor 1
Necrotizing Enterocolitis
Wounds and Injuries
Nutritional Support
Somatomedins
Therapeutics
Insulin-Like Growth Factor I
Premature Infants
Caspase 3
Small Interfering RNA
Intercellular Signaling Peptides and Proteins
Proteins
Transcription Factors

ASJC Scopus subject areas

  • Surgery

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Phosphatidylinositol 3-kinase pathway regulates hypoxia-inducible factor-1 to protect from intestinal injury during necrotizing enterocolitis. / Baregamian, Naira; Rychahou, Piotr G.; Hawkins, Hal K.; Evers, B. Mark; Chung, Dai H.

In: Surgery, Vol. 142, No. 2, 08.2007, p. 295-302.

Research output: Contribution to journalArticle

Baregamian, Naira ; Rychahou, Piotr G. ; Hawkins, Hal K. ; Evers, B. Mark ; Chung, Dai H. / Phosphatidylinositol 3-kinase pathway regulates hypoxia-inducible factor-1 to protect from intestinal injury during necrotizing enterocolitis. In: Surgery. 2007 ; Vol. 142, No. 2. pp. 295-302.
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abstract = "Background: Hypoxia is an important risk factor for development of necrotizing enterocolitis (NEC) in premature infants. Hypoxia-inducible factor (HIF)-1 is a transcription factor that plays a critical role in cellular responses to hypoxia and can be induced by phosphatidylinositol 3-kinase (PI3-K) pathway. Activation of the PI3-K and regulation of HIF-1 during NEC have not been elucidated. Methods: NEC was induced in 3-day-old neonatal mice using hypoxia and artificial formula feedings. Mice were divided into 3 treatment groups: (1) NEC alone, (2) NEC with insulin-like growth factor (IGF)-I, or (3) NEC with Akt1 siRNA treatment. Animals were sacrificed, and intestinal sections were harvested for protein analysis, H&E, and immunohistochemical staining. Results: In vivo model of NEC produced intestinal injury associated with increased protein expression of HIF-1α, pAkt, PARP, and caspase-3 cleavage. Pretreatment with IGF-1 attenuated an HIF-1α response. In contrast, targeted inhibition of Akt1 completely abolished NEC-induced expression of pAkt and upregulated HIF-1α activation. Conclusions: NEC activates important protective cellular responses to hypoxic injury such as HIF-1α and PI3-K/Akt in neonatal gut. Hypoxia-mediated activation of pro-survival signaling during NEC may be modulated with growth factors, which thus suggests a potential therapeutic option in the treatment of neonates with NEC.",
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AB - Background: Hypoxia is an important risk factor for development of necrotizing enterocolitis (NEC) in premature infants. Hypoxia-inducible factor (HIF)-1 is a transcription factor that plays a critical role in cellular responses to hypoxia and can be induced by phosphatidylinositol 3-kinase (PI3-K) pathway. Activation of the PI3-K and regulation of HIF-1 during NEC have not been elucidated. Methods: NEC was induced in 3-day-old neonatal mice using hypoxia and artificial formula feedings. Mice were divided into 3 treatment groups: (1) NEC alone, (2) NEC with insulin-like growth factor (IGF)-I, or (3) NEC with Akt1 siRNA treatment. Animals were sacrificed, and intestinal sections were harvested for protein analysis, H&E, and immunohistochemical staining. Results: In vivo model of NEC produced intestinal injury associated with increased protein expression of HIF-1α, pAkt, PARP, and caspase-3 cleavage. Pretreatment with IGF-1 attenuated an HIF-1α response. In contrast, targeted inhibition of Akt1 completely abolished NEC-induced expression of pAkt and upregulated HIF-1α activation. Conclusions: NEC activates important protective cellular responses to hypoxic injury such as HIF-1α and PI3-K/Akt in neonatal gut. Hypoxia-mediated activation of pro-survival signaling during NEC may be modulated with growth factors, which thus suggests a potential therapeutic option in the treatment of neonates with NEC.

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