title: Loss of NRF2 impairs gastric nitrergic stimulation and function.
abstract: Emerging research suggests that antioxidant gene expression has the potential to suppress the development of gastroparesis. However, direct genetic evidence that definitively supports this concept is lacking. We used mice carrying a targeted disruption of Nfe2l2, the gene that encodes the transcription factor NRF2 and directs antioxidant Phase II gene expression, as well as mice with a targeted disruption of Gclm, the modifier subunit for glutamate-cysteine ligase, to test the hypothesis that defective antioxidant gene expression contributes to development of gastroparesis. Although expression of heme oxygenase-1 remained unchanged, expression of GCLC, GCLM, SOD1, and CAT was down-regulated in gastric tissue from Nrf2(-/-) mice compared to wild-type animals. Tetrahydrobiopterin oxidation was significantly elevated and nitrergic relaxation was impaired in Nrf2(-/-) mouse gastric tissue. In vitro studies showed a significant decrease in NO release in Nrf2(-/-) mouse gastric tissue. Nrf2(-/-) mice displayed delayed gastric emptying. The use of Gclm(-/-) mice demonstrated that the loss of glutamate-cysteine ligase function enhanced tetrahydrobiopterin oxidation while impairing nitrergic relaxation. These results provide genetic evidence that loss of antioxidant gene expression can contribute to the development of gastroparesis and suggest that NRF2 represents a potential therapeutic target.
authors: Department of Physiology, Meharry Medical College, Nashville, TN 37208, USA.
authors: Sutapa
authors: S
authors: Mukhopadhyay
authors: Konjeti R
authors: KR
authors: Sekhar
authors: Ashley B
authors: AB
authors: Hale
authors: Keith M
authors: KM
authors: Channon
authors: Gianrico
authors: G
authors: Farrugia
authors: Michael L
authors: ML
authors: Freeman
authors: Pandu R
authors: PR
authors: Gangula
references: Cell. 1994 Sep 23;78(6):915-8
references: 7522969
references: Gastroenterol Hepatol (N Y). 2010 Jun;6(6):1-16
references: 20733935
references: Gastroenterology. 2011 May;140(5):1575-85.e8
references: 21300066
references: Gastroenterology. 2011 Jan;140(1):101-15
references: 20965184
references: J Biol Chem. 2000 Jun 9;275(23):17407-11
references: 10751385
references: Cell. 1998 Dec 23;95(7):939-50
references: 9875848
references: Free Radic Biol Med. 2011 Sep 1;51(5):993-9
references: 21163347
references: Sci Signal. 2010 Mar 09;3(112):re3
references: 20215646
references: J Biol Chem. 1999 Sep 10;274(37):26071-8
references: 10473555
references: J Biol Chem. 2003 Jun 20;278(25):22546-54
references: 12692136
references: Neurogastroenterol Motil. 2010 Dec;22(12):1325-31, e351-2
references: 20731778
references: Gastroenterology. 2008 Dec;135(6):2055-64, 2064.e1-2
references: 18926825
references: Gastroenterology. 2010 Jun;138(7):2399-409, 2409.e1
references: 20178793
references: J Biol Chem. 2009 Jan 9;284(2):1136-44
references: 19011239
references: Am J Respir Crit Care Med. 2009 Dec 15;180(12):1196-207
references: 19797762
references: Gut. 2010 Dec;59(12):1716-26
references: 20871131
references: FASEB J. 2007 Jul;21(9):2237-46
references: 17384144
references: Am J Physiol Gastrointest Liver Physiol. 2010 May;298(5):G692-9
references: 20185690
references: Drugs. 2009 May 29;69(8):971-86
references: 19496627
references: Adv Pharmacol. 2010;60:107-32
references: 21081217
references: J Cell Physiol. 2000 Feb;182(2):163-70
references: 10623879
references: Nucleic Acids Res. 2010 Sep;38(17):5718-34
references: 20460467
references: Annu Rev Pharmacol Toxicol. 1997;37:339-59
references: 9131257
references: Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14960-5
references: 8962164
references: Free Radic Biol Med. 2011 Mar 1;50(5):567-75
references: 21163346
references: J Biol Chem. 2002 Dec 20;277(51):49446-52
references: 12384496
references: Antioxid Redox Signal. 2005 Nov-Dec;7(11-12):1674-87
references: 16356129
references: Biochem Biophys Res Commun. 1999 Aug 11;261(3):661-8
references: 10441483
references: Cancer Res. 2001 Apr 15;61(8):3299-307
references: 11309284
references: J Biol Chem. 2008 Apr 25;283(17):11734-42
references: 18283102
references: J Gastroenterol Hepatol. 2011 Jan;26 Suppl 1:46-57
references: 21199514
references: Free Radic Biol Med. 2003 May 15;34(10):1236-42
references: 12726911
references: Am J Physiol Gastrointest Liver Physiol. 2007 Mar;292(3):G725-33
references: 17347455
references: J Biol Chem. 2003 Mar 7;278(10):8135-45
references: 12506115
references: Biochem Soc Trans. 2000 Feb;28(2):33-41
references: 10816095
references: Mol Genet Metab. 2010 Sep;101(1):55-61
references: 20655259
references: Nat Clin Pract Gastroenterol Hepatol. 2007 Jun;4(6):336-46
references: 17541447