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Fas (CD95) alters neuronal nitric oxide synthase expression to contribute in diabetic gastroparesis
Correspondence
1427
Fas (CD95) alters neuronal nitric oxide synthase expression to contribute in diabetic gastroparesis Type 2 diabetes mellitus or non-insulin-dependent diabetes is caused by various factors including obesity. Chronic hyperglycemia is detrimental to pancreatic beta-cells, causing impaired insulin secretion and playing an essential role in the regulation of beta-cell turnover [1]. These changes lead to several complications including enteric neurodegeneration. Enteric neuron contains potential neurotransmitters, which include 5-hydroxytryptamine (5HT)/serotonin, substance P (SP), vasoactive intestinal peptide (VIP), nitric oxide synthase (nNOS) [2] and acetylcholine, to regulate contraction and relaxation of the gastrointestine. Hence enteric neurodegeneration would affect normal gastric emptying. Delayed gastric emptying/gastroparesis is one of the events seen in diabetes [3]. Therefore it is important to understand molecular mechanism involved in diabetic gastroparesis. Fas (Tnfrsf6/CD95/APO1) is a member of a family of transmembrane cell surface protein. Upregualtion of fas and fas ligand has been found during various cell death including nerve cells. Fas induces cell death via either apoptosis or necrosis [4]. Fas alters normal transcription of neuronal nitric oxide synthase (nNOS) [5]. Increased levels of nNOS contribute to necrotic cell death [6] and downregulation of nNOS contribute to apoptosis [2]. These signals are modulated by sex hormones [7]. These studies suggest that sex hormones inducing fas expression alters normal expression of nNOS to lead cell death. The level of fas protein is high in the enteric neurons and fas ligands are upregulated in the stomach and duodenum during type 2 diabetic condition. Normal expression of nNOS was also found to be altered in the duodenum of type 2 diabetes mouse [2]. These studies suggest that hyperglycemic condition likely affects sex hormones to upregulate fas and doi:10.1016/j.mehy.2006.11.001
subsequently alters normal levels of nNOS expression to lead enteric neurodegeneration. These changes are atleast partly ascribable to gastroparesis seen in diabetes.
References [1] Maedler K, Donath MY. Beta-cells in type 2 diabetes: a loss of function and mass. Horm Res 2004;62(Suppl. 3): 67–73. [2] Surendran S, Kondapaka SB. Altered expression of neuronal nitric oxide synthase in the duodenum longitudinal musclemyenteric plexus of obesity induced diabetes mouse: implications on enteric neurodegeneration. Biochem Biophys Res Commun 2005;338:919–22. [3] Anonymous, Gastrointestinal motility disorders and therapy. How diabetes paralyzes the intestine, MMW Fortschr Med;2005. 147, p. 8. [4] Surendran S. Possible role of fas antigen (CD 95) in human amniotic epithelial cell death: an in vitro study. Cell Biol Int 2001;25:485–8. [5] Raoul C, Barthelemy C, Couzinet A, Hancock D, Pettmann B, Hueber A. Expression of a dominant negative form of daxx in vivo rescues motoneurons from fas (CD95)-induced cell death. J Neurobiol 2005;62:178–88. [6] Rinecker M, Plesnila N, Baethmann A, Stoffel M. Secondary growth of a cortical necrosis: effect of NOS inhibition by aminoguanidine post insult. Acta Neurochir (Wien) 2003;145: 977–81. [7] Song J, Rutherford T, Naftolin F, Brown S, Mor G. Hormonal regulation of apoptosis and the fas and fas ligand system in human endometrial cells. Mol Hum Reprod 2002;8:447–55.
Sankar Surendran Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 77555, USA Tel.: +1 409 772 112 E-mail addresses: [email protected], [email protected]
1427
Fas (CD95) alters neuronal nitric oxide synthase expression to contribute in diabetic gastroparesis Type 2 diabetes mellitus or non-insulin-dependent diabetes is caused by various factors including obesity. Chronic hyperglycemia is detrimental to pancreatic beta-cells, causing impaired insulin secretion and playing an essential role in the regulation of beta-cell turnover [1]. These changes lead to several complications including enteric neurodegeneration. Enteric neuron contains potential neurotransmitters, which include 5-hydroxytryptamine (5HT)/serotonin, substance P (SP), vasoactive intestinal peptide (VIP), nitric oxide synthase (nNOS) [2] and acetylcholine, to regulate contraction and relaxation of the gastrointestine. Hence enteric neurodegeneration would affect normal gastric emptying. Delayed gastric emptying/gastroparesis is one of the events seen in diabetes [3]. Therefore it is important to understand molecular mechanism involved in diabetic gastroparesis. Fas (Tnfrsf6/CD95/APO1) is a member of a family of transmembrane cell surface protein. Upregualtion of fas and fas ligand has been found during various cell death including nerve cells. Fas induces cell death via either apoptosis or necrosis [4]. Fas alters normal transcription of neuronal nitric oxide synthase (nNOS) [5]. Increased levels of nNOS contribute to necrotic cell death [6] and downregulation of nNOS contribute to apoptosis [2]. These signals are modulated by sex hormones [7]. These studies suggest that sex hormones inducing fas expression alters normal expression of nNOS to lead cell death. The level of fas protein is high in the enteric neurons and fas ligands are upregulated in the stomach and duodenum during type 2 diabetic condition. Normal expression of nNOS was also found to be altered in the duodenum of type 2 diabetes mouse [2]. These studies suggest that hyperglycemic condition likely affects sex hormones to upregulate fas and doi:10.1016/j.mehy.2006.11.001
subsequently alters normal levels of nNOS expression to lead enteric neurodegeneration. These changes are atleast partly ascribable to gastroparesis seen in diabetes.
References [1] Maedler K, Donath MY. Beta-cells in type 2 diabetes: a loss of function and mass. Horm Res 2004;62(Suppl. 3): 67–73. [2] Surendran S, Kondapaka SB. Altered expression of neuronal nitric oxide synthase in the duodenum longitudinal musclemyenteric plexus of obesity induced diabetes mouse: implications on enteric neurodegeneration. Biochem Biophys Res Commun 2005;338:919–22. [3] Anonymous, Gastrointestinal motility disorders and therapy. How diabetes paralyzes the intestine, MMW Fortschr Med;2005. 147, p. 8. [4] Surendran S. Possible role of fas antigen (CD 95) in human amniotic epithelial cell death: an in vitro study. Cell Biol Int 2001;25:485–8. [5] Raoul C, Barthelemy C, Couzinet A, Hancock D, Pettmann B, Hueber A. Expression of a dominant negative form of daxx in vivo rescues motoneurons from fas (CD95)-induced cell death. J Neurobiol 2005;62:178–88. [6] Rinecker M, Plesnila N, Baethmann A, Stoffel M. Secondary growth of a cortical necrosis: effect of NOS inhibition by aminoguanidine post insult. Acta Neurochir (Wien) 2003;145: 977–81. [7] Song J, Rutherford T, Naftolin F, Brown S, Mor G. Hormonal regulation of apoptosis and the fas and fas ligand system in human endometrial cells. Mol Hum Reprod 2002;8:447–55.
Sankar Surendran Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 77555, USA Tel.: +1 409 772 112 E-mail addresses: [email protected], [email protected]