| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
prevents oxidant-induced iNOS upregulation and protects
the microtubules and gut barrier integrity
1 Departments of Internal Medicine (Section of Gastroenterology and Nutrition), Pharmacology, and Molecular Physiology, Rush University Medical Center, Chicago, Illinois 60612; and 2 Institute of Human Nutrition, Columbia University, New York, New York 10032
Using intestinal (Caco-2) monolayers,
we reported that inducible nitric oxide synthase (iNOS) activation is
key to oxidant-induced barrier disruption and that EGF protects against
this injury. PKC-
was required for protection. We thus hypothesized
that PKC- activation and iNOS inactivation are key in EGF
protection. Wild-type (WT) Caco-2 cells were exposed to
H2O2 (0.5 mM) ± EGF or PKC modulators. Other cells were transfected to overexpress PKC- or to inhibit it
and then pretreated with EGF or a PKC activator (OAG) before oxidant. Relative to WT cells exposed to oxidant, pretreatment with EGF protected monolayers by 1) increasing PKC-
activity; 2) decreasing iNOS activity and protein, NO
levels, oxidative stress, tubulin oxidation, and nitration);
3) increasing polymerized tubulin; 4) maintaining
the cytoarchitecture of microtubules; and 5) enhancing
barrier integrity. Relative to WT cells exposed to oxidant, transfected
cells overexpressing PKC- (+2.9-fold) were protected as
indicated by decreases in all measures of iNOS-driven pathways and
enhanced stability of microtubules and barrier function. Overexpression-induced inhibition of iNOS was OAG independent, but EGF
potentiated this protection. Antisense inhibition of PKC- (
95%)
prevented all measures of EGF protection against iNOS upregulation. Thus EGF protects against oxidative disruption of the intestinal barrier by stabilizing the cytoskeleton in large part through the
activation of PKC- and downregulation of iNOS. Activation of PKC-
is by itself required for cellular protection against oxidative stress
of iNOS. We have thus discovered novel biologic functions, suppression
of the iNOS-driven reactions and cytoskeletal oxidation, among the
atypical PKC isoforms.
tubulin cytoskeleton; growth factors; oxidative stress; nitrogen metabolites; molecular biology; inflammatory bowel disease
This article has been cited by other articles:
|
|
 |
|
  V. A. Swystun, B. Renaux, F. Moreau, S. Wen, M. A. Peplowski, M. D. Hollenberg, and W. K. MacNaughton Serine proteases decrease intestinal epithelial ion permeability by activation of protein kinase C{zeta} Am J Physiol Gastrointest Liver Physiol, July 1, 2009; 297(1): G60 - G70. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Fu, Z. Wang, W. L. Chen, P. K. Moore, and Y. Z. Zhu Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1545 - H1552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Farhadi, A. Keshavarzian, Z. Ranjbaran, J. Z. Fields, and A. Banan The Role of Protein Kinase C Isoforms in Modulating Injury and Repair of the Intestinal Barrier J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 1 - 7. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Fleegal, S. Hom, L. K. Borg, and T. P. Davis Activation of PKC modulates blood-brain barrier endothelial cell permeability changes induced by hypoxia and posthypoxic reoxygenation Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2012 - H2019. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Banan, L. J. Zhang, A. Farhadi, J. Z. Fields, M. Shaikh, C. B. Forsyth, S. Choudhary, and A. Keshavarzian Critical Role of the Atypical {lambda} Isoform of Protein Kinase C (PKC-{lambda}) in Oxidant-Induced Disruption of the Microtubule Cytoskeleton and Barrier Function of Intestinal Epithelium J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 458 - 471. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Banan, L. J. Zhang, M. Shaikh, J. Z. Fields, A. Farhadi, and A. Keshavarzian Novel effect of NF-{kappa}B activation: carbonylation and nitration injury to cytoskeleton and disruption of monolayer barrier in intestinal epithelium Am J Physiol Cell Physiol, October 1, 2004; 287(4): C1139 - C1151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Banan, L. J. Zhang, M. Shaikh, J. Z. Fields, A. Farhadi, and A. Keshavarzian Key role of PLC-{gamma} in EGF protection of epithelial barrier against iNOS upregulation and F-actin nitration and disassembly Am J Physiol Cell Physiol, October 1, 2003; 285(4): C977 - C993. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Badorff and S. Dimmeler NO Balance: Regulation of the Cytoskeleton in Congestive Heart Failure by Nitric Oxide Circulation, March 18, 2003; 107(10): 1348 - 1349. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
