Phosphatidylinositol 3-kinase pathway regulates hypoxia-inducible factor-1 to protect from intestinal injury during necrotizing enterocolitis.
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-1alpha, pAkt, PARP, and caspase-3 cleavage. Pretreatment with IGF-1 attenuated an HIF-1alpha response. In contrast, targeted inhibition of Akt1 completely abolished NEC-induced expression of pAkt and upregulated HIF-1alpha activation.


CONCLUSIONS
NEC activates important protective cellular responses to hypoxic injury such as HIF-1alpha 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.
Baregamian
Naira
N
Department of Surgery, The University of Texas Medical Branch, Galveston, Tex, USA.
Rychahou
Piotr G
PG
Hawkins
Hal K
HK
Evers
B Mark
BM
Chung
Dai H
DH
D000818:Animals; D000831:Animals, Newborn; D020345:Enterocolitis, Necrotizing / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D015996:Survival Rate; D015854:Up-Regulation / Q000502:physiology
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
Genes Dev. 2000 Feb 15;14(4):391-6
10691731
J Surg Res. 2006 Nov;136(1):31-7
16999977
J Biol Chem. 2000 Aug 18;275(33):25130-8
10833514
Cancer Res. 2001 Mar 15;61(6):2429-33
11289110
Cell Growth Differ. 2001 Jul;12(7):363-9
11457733
Biochem Biophys Res Commun. 2001 Sep 14;287(1):292-300
11549290
J Biol Chem. 2002 Oct 11;277(41):38205-11
12149254
J Neurosci. 2002 Oct 15;22(20):8922-31
12388599
J Biol Chem. 2003 Aug 15;278(33):31277-85
12764143
Melanoma Res. 2003 Oct;13(5):493-501
14512791
Pediatr Res. 2004 Mar;55(3):385-94
14711902
FASEB J. 2004 Sep;18(12):1348-65
15333578
J Clin Pathol. 2004 Oct;57(10):1009-14
15452150
Anal Biochem. 1976 May 7;72:248-54
942051
Pediatr Pathol. 1988;8(2):151-62
3413001
Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11715-20
9751731
Mol Endocrinol. 2005 May;19(5):1304-17
15695372
Mol Cell Biol. 2005 Jun;25(12):4853-62
15923604
Biochim Biophys Acta. 2005 Jul 25;1755(2):107-20
15994012
Minerva Anestesiol. 2005 Nov;71(11):727-40
16278632
Pediatr Res. 2005 Dec;58(6):1192-7
16306192
Crit Care Med. 2005 Dec;33(12 Suppl):S423-5
16340411
EMBO Rep. 2006 Jan;7(1):41-5
16391536
Mol Cancer Res. 2003 Feb;1(4):312-22
12612059
Cancer Res. 2000 Mar 15;60(6):1541-5
10749120