Vasoactive intestinal peptide reduces oxidative stress in pancreatic acinar cells through the inhibition of NADPH oxidase

• Published in: Peptides (New York, N.Y. : 1980) Vol. 32; no. 10; pp. 2067 - 2076
• Main Authors: Fujimori, Nao, Oono, Takamasa, Igarashi, Hisato, Ito, Tetsuhide, Nakamura, Taichi, Uchida, Masahiko, Coy, David H., Jensen, Robert T., Takayanagi, Ryoichi
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-10-2011; Elsevier
• Subjects: acinar cells; Acinar Cells - cytology; Acinar Cells - drug effects; Acinar Cells - metabolism; Animals; Antioxidant; antioxidants; Biological and medical sciences; cAMP-dependent protein kinase; catalase; cell viability; Cells, Cultured; cyclic AMP; cytokines; dose response; Fundamental and applied biological sciences. Psychology; glutathione peroxidase; glutathione-disulfide reductase; hydrogen peroxide; Male; NAD(P)H oxidase (H2O2-forming); NADP (coenzyme); NADPH oxidase; NADPH Oxidases - antagonists & inhibitors; NADPH Oxidases - metabolism; oxidative stress; Oxidative Stress - drug effects; pancreas; Pancreas, Exocrine - cytology; pancreatitis; pathophysiology; protective effect; Rats; Rats, Inbred Lew; Reactive oxygen species; Reactive Oxygen Species - metabolism; superoxide dismutase; Vasoactive intestinal peptide; Vasoactive Intestinal Peptide - analogs & derivatives; Vasoactive Intestinal Peptide - metabolism; Vasoactive Intestinal Peptide - pharmacology; Vertebrates: endocrinology; Reactive oxygen species; NADPH oxidase; ROS; PKA; Vasoactive intestinal peptide; SOD; VIP; H2O2; cAMP; Antioxidant; AP; Oxidative stress; Oxygen; Digestive system; Exocrine pancreas; Peptide hormone; Acinus; Inhibition
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2011.08.027

► Oxidative stress by H2O2 increased reactive oxygen species (ROS) in acini. ► ROS increased dose-dependently in damaged acini, thereby reducing the viability. ► Vasoactive intestinal peptide (VIP) reduced ROS and ameliorated cell viability. ► VIP up-regulated superoxide dismutase (SOD) 2 and inhibited NADPH oxidase activity. ► VIP affects the mechanism of ROS production through induction of cAMP/PKA pathway.
Vasoactive intestinal peptide (VIP) attenuates experimental acute pancreatitis (AP) by inhibition of cytokine production from inflammatory cells. It has been suggested that reactive oxygen species (ROS) as well as cytokines play pivotal roles in the early pathophysiology of AP. This study aimed to clarify the effect of VIP on the oxidative condition in pancreas, especially pancreatic acinar cells (acini). Hydrogen peroxide (H2O2)-induced intracellular ROS, assessed with CM-H2DCFDA, increased time- and dose-dependently in acini isolated from rats. Cell viability due to ROS-induced cellular damage, evaluated by MTS assay, was decreased with ≥100μmol/L H2O2. VIP significantly inhibited ROS production from acini and increased cell viability in a dose-dependent manner. Expression of antioxidants including catalase, glutathione reductase, superoxide dismutase (SOD) 1 and glutathione peroxidase was not altered by VIP except for SOD2. Furthermore, Nox1 and Nox2, major components of NADPH oxidase, were expressed in pancreatic acini, and significantly increased after H2O2 treatment. Also, NADPH oxidase activity was provoked by H2O2. VIP decreased NADPH oxidase activity, which was abolished by PKA inhibitor H89. These results suggested that VIP affected the mechanism of ROS production including NADPH oxidase through induction of a cAMP/PKA pathway. In conclusion, VIP reduces oxidative stress in acini through the inhibition of NADPH oxidase. These results combined with findings of our previous study suggest that VIP exerts its protective effect in pancreatic damage, not only through an inhibition of cytokine production, but also through a reduction of the injury caused by oxidative stress.