PMID- 23684565
OWN - NLM
STAT- MEDLINE
DCOM- 20140328
LR  - 20220223
IS  - 1089-8611 (Electronic)
IS  - 1089-8603 (Print)
IS  - 1089-8603 (Linking)
VI  - 33
DP  - 2013 Sep 1
TI  - Contribution of iNOS/sGC/PKG pathway, COX-2, CYP4A1, and gp91(phox) to the 
      protective effect of 5,14-HEDGE, a 20-HETE mimetic, against vasodilation, 
      hypotension, tachycardia, and inflammation in a rat model of septic shock.
PG  - 18-41
LID - S1089-8603(13)00145-6 [pii]
LID - 10.1016/j.niox.2013.05.001 [doi]
AB  - We have previously demonstrated that a stable synthetic analog of 
      20-hydroxyeicosatetraenoic acid (20-HETE), 
      N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-HEDGE), prevents vascular 
      hyporeactivity, hypotension, tachycardia, and inflammation in rats treated with 
      lipopolysaccharide (LPS) and mortality in endotoxemic mice. These changes were 
      attributed to decreased production of inducible nitric oxide (NO) synthase 
      (iNOS)-derived NO, cyclooxygenase (COX)-2-derived vasodilator prostanoids, and 
      proinflammatory mediators associated with increased cyctochrome P450 (CYP) 
      4A1-derived 20-HETE and CYP2C23-dependent antiinflammatory mediator formation. 
      The aim of this study was to determine whether decreased expression and activity 
      of iNOS, soluble guanylyl cyclase (sGC), protein kinase G (PKG), COX-2, 
      gp91(phox) (NOX2; a superoxide generating NOX enzyme), and peroxynitrite 
      production associated with increased expression of COX-1 and CYP4A1 and 20-HETE 
      formation in renal and cardiovascular tissues of rats contributes to the effect 
      of 5,14-HEDGE to prevent vasodilation, hypotension, tachycardia, and inflammation 
      in response to systemic administration of LPS. Mean arterial pressure fell by 
      28mmHg and heart rate rose by 47beats/min in LPS (10mg/kg, i.p.)-treated rats. 
      Administration of LPS also increased mRNA and protein expression of iNOS and 
      COX-2 associated with a decrease in COX-1 and CYP4A1 mRNA and protein expression. 
      Increased NOS activity, iNOS-heat shock protein 90 complex formation (an index 
      for iNOS activity), protein expression of phosphorylated vasodilator stimulated 
      phosphoprotein (an index for PKG activity), gp91(phox), p47(phox) (NOXO2; 
      organizer subunit of gp91(phox)), and nitrotyrosine (an index for peroxynitrite 
      production) as well as cGMP (an index for sGC activity), 6-keto-PGF1alpha (a stable 
      metabolite PGI2) and PGE2 levels (indexes for COX activity), and nitrotyrosine 
      levels by LPS were also associated with decreased CYP hydroxylase activity as 
      measured by 20-HETE formation from arachidonic acid in renal microsomes of 
      LPS-treated rats. These effects of LPS, except iNOS mRNA and COX-1 protein 
      expression, were prevented by 5,14-HEDGE (30mg/kg, s.c.; 1h after LPS). A 
      competitive antagonist of vasoconstrictor effects of 20-HETE, 
      20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (30mg/kg, s.c.; 1h after LPS) reversed 
      the effects of 5,14-HEDGE, except iNOS and COX-1 mRNA and protein expression as 
      well as expression of CYP4A1 mRNA. These results suggest that increased CYP4A1 
      expression and 20-HETE formation associated with suppression of iNOS/sGC/PKG 
      pathway, COX-2, and gp91(phox) participate in the protective effect of 5,14-HEDGE 
      against vasodilation, hypotension, tachycardia, and inflammation in the rat model 
      of septic shock.
CI  - Copyright (c) 2013 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Tunctan, Bahar
AU  - Tunctan B
AD  - Department of Pharmacology, Faculty of Pharmacy, Mersin University, 33169 Mersin, 
      Turkey. tunctanb@yahoo.com
FAU - Korkmaz, Belma
AU  - Korkmaz B
FAU - Sari, Ayse Nihal
AU  - Sari AN
FAU - Kacan, Meltem
AU  - Kacan M
FAU - Unsal, Demet
AU  - Unsal D
FAU - Serin, Mehmet Sami
AU  - Serin MS
FAU - Buharalioglu, C Kemal
AU  - Buharalioglu CK
FAU - Sahan-Firat, Seyhan
AU  - Sahan-Firat S
FAU - Cuez, Tuba
AU  - Cuez T
FAU - Schunck, Wolf-Hagen
AU  - Schunck WH
FAU - Manthati, Vijaya L
AU  - Manthati VL
FAU - Falck, John R
AU  - Falck JR
FAU - Malik, Kafait U
AU  - Malik KU
LA  - eng
GR  - P01 DK038226/DK/NIDDK NIH HHS/United States
GR  - R01 HL019134/HL/NHLBI NIH HHS/United States
GR  - DK38226/DK/NIDDK NIH HHS/United States
GR  - 19134-37/PHS HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130514
PL  - United States
TA  - Nitric Oxide
JT  - Nitric oxide : biology and chemistry
JID - 9709307
RN  - 0 (20-hydroxyeicosa-6(Z),15(Z)-dienoic acid)
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Cyp2c23 protein, rat)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (Hydroxyeicosatetraenoic Acids)
RN  - 0 (Lipopeptides)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Microfilament Proteins)
RN  - 0 (N-(20-hydroxyeicosa-5,14-dienoyl)glycine)
RN  - 0 (Phosphoproteins)
RN  - 0 (Protective Agents)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (vasodilator-stimulated phosphoprotein)
RN  - 14691-52-2 (Peroxynitrous Acid)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 1.14.13.39 (Nos2 protein, rat)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2J2)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 1.6.3.- (Cybb protein, rat)
RN  - EC 1.6.3.- (NADPH Oxidase 2)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases)
RN  - EC 4.6.1.2 (Guanylate Cyclase)
RN  - EC 4.6.1.2 (Soluble Guanylyl Cyclase)
SB  - IM
MH  - Animals
MH  - Cell Adhesion Molecules/metabolism
MH  - Cyclic GMP-Dependent Protein Kinases/metabolism
MH  - Cyclooxygenase 2/genetics/metabolism
MH  - Cytochrome P-450 CYP2J2
MH  - Cytochrome P-450 Enzyme System/genetics/metabolism
MH  - Disease Models, Animal
MH  - Guanylate Cyclase/metabolism
MH  - HSP90 Heat-Shock Proteins/metabolism
MH  - Hydroxyeicosatetraenoic Acids/pharmacology
MH  - Lipopeptides/*pharmacology
MH  - Lipopolysaccharides/pharmacology
MH  - Male
MH  - Membrane Glycoproteins/metabolism
MH  - Microfilament Proteins/metabolism
MH  - NADPH Oxidase 2
MH  - NADPH Oxidases/metabolism
MH  - Nitric Oxide Synthase Type II/genetics/*metabolism
MH  - Organ Specificity
MH  - Peroxynitrous Acid/metabolism
MH  - Phosphoproteins/metabolism
MH  - Protective Agents/*pharmacology
MH  - RNA, Messenger/genetics/metabolism
MH  - Random Allocation
MH  - Rats
MH  - Rats, Wistar
MH  - Receptors, Cytoplasmic and Nuclear/metabolism
MH  - Shock, Septic/*drug therapy/enzymology/genetics/*metabolism
MH  - Signal Transduction/*drug effects
MH  - Soluble Guanylyl Cyclase
PMC - PMC3759626
MID - NIHMS482252
OTO - NOTNLM
OT  - 1,3-PBIT
OT  - 20-HEDE
OT  - 20-HETE
OT  - 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid
OT  - 20-hydroxyeicosatetraenoic acid
OT  - 5,14-HEDGE
OT  - AA
OT  - COX
OT  - COX-2
OT  - CYP
OT  - CYP4A1
OT  - EET
OT  - ELISA
OT  - ERK
OT  - Endotoxin
OT  - HR
OT  - Hypotension
OT  - IKK
OT  - IL
OT  - IkappaB
OT  - IkappaB kinase
OT  - LPS
OT  - MAP
OT  - MAPK
OT  - MEK
OT  - N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine
OT  - NADPH
OT  - NF-kappaB
OT  - NO
OT  - PG
OT  - PKG
OT  - RT-PCR
OT  - TNF
OT  - VASP
OT  - arachidonic acid
OT  - cDNA
OT  - cGMP
OT  - complementary deoxyribonucleic acid
OT  - cyclic guanosine monophosphate
OT  - cyclooxygenase
OT  - cyctochrome P450
OT  - eNOS
OT  - endothelial nitric oxide synthase
OT  - enzyme-linked immunosorbent assay
OT  - epoxyeicosatrienoic acid
OT  - extracellular signal-regulated kinase
OT  - gp91(phox)/NOX2
OT  - heart rate
OT  - heat shock protein
OT  - hsp
OT  - i.p.
OT  - iNOS
OT  - iNOS/sGC/PKG pathway
OT  - inducible nitric oxide synthase
OT  - inhibitor of kappaB
OT  - interleukin
OT  - intraperitoneally
OT  - lipopolysaccharide
OT  - mRNA
OT  - mean arterial pressure
OT  - messenger ribonucleic acid
OT  - mitogen-activated protein kinase
OT  - mitogen-activated protein kinase kinase 1
OT  - nicotinamide adenine dinucleotide phosphate
OT  - nitric oxide
OT  - nuclear factor-kappaB
OT  - p-VASP
OT  - phenylene-1,3-bis(ethane-2-isothiourea) dihydrobromide
OT  - phosphorylated vasodilator stimulated phosphoprotein
OT  - prostaglandin
OT  - protein kinase G
OT  - reverse transcription-polymerase chain reaction
OT  - s.c.
OT  - sEH
OT  - sGC
OT  - soluble epoxide hydrolase
OT  - soluble guanylyl cyclase
OT  - subcutaneously
OT  - tumor necrosis factor
OT  - vasodilator stimulated phosphoprotein
EDAT- 2013/05/21 06:00
MHDA- 2014/03/29 06:00
PMCR- 2014/09/01
CRDT- 2013/05/21 06:00
PHST- 2013/01/02 00:00 [received]
PHST- 2013/04/23 00:00 [revised]
PHST- 2013/05/07 00:00 [accepted]
PHST- 2013/05/21 06:00 [entrez]
PHST- 2013/05/21 06:00 [pubmed]
PHST- 2014/03/29 06:00 [medline]
PHST- 2014/09/01 00:00 [pmc-release]
AID - S1089-8603(13)00145-6 [pii]
AID - 10.1016/j.niox.2013.05.001 [doi]
PST - ppublish
SO  - Nitric Oxide. 2013 Sep 1;33:18-41. doi: 10.1016/j.niox.2013.05.001. Epub 2013 May 
      14.