Contribution of iNOS/sGC/PKG pathway, COX-2, CYP4A1, and gp91phox 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☆
| Autor: | Meltem Kacan, Mehmet Sami Serin, Seyhan Sahan-Firat, Tuba Cuez, Wolf-Hagen Schunck, Demet Unsal, Bahar Tunctan, Belma Korkmaz, Ayse Nihal Sari, C. Kemal Buharalioglu, John R. Falck, Vijaya L. Manthati, Kafait U. Malik |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Lipopolysaccharides
Male Cancer Research Physiology Clinical Biochemistry Nitric Oxide Synthase Type II Receptors Cytoplasmic and Nuclear Biochemistry Cytochrome P-450 CYP2J2 chemistry.chemical_compound Random Allocation Soluble Guanylyl Cyclase Endotoxin Cytochrome P-450 Enzyme System Hydroxyeicosatetraenoic Acids Membrane Glycoproteins biology Nitrotyrosine Microfilament Proteins iNOS/sGC/PKG pathway 20-Hydroxyeicosatetraenoic acid Shock Septic Organ Specificity NADPH Oxidase 2 cardiovascular system lipids (amino acids peptides and proteins) Hypotension Peroxynitrite Signal Transduction medicine.medical_specialty CYP4A1 Protective Agents Article Nitric oxide Lipopeptides Internal medicine Peroxynitrous Acid medicine Cyclic GMP-Dependent Protein Kinases gp91phox/NOX2 Animals HSP90 Heat-Shock Proteins RNA Messenger Rats Wistar Vasodilator-stimulated phosphoprotein NADPH Oxidases COX-2 Phosphoproteins Rats Disease Models Animal Endocrinology chemistry Cyclooxygenase 2 Guanylate Cyclase biology.protein Cyclooxygenase Soluble guanylyl cyclase cGMP-dependent protein kinase Cell Adhesion Molecules |
| Popis: | 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 28 mmHg and heart rate rose by 47 beats/min in LPS (10 mg/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-PGFic, (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 (30 mg/kg, s.c.; 1 h after LPS). A competitive antagonist of vasoconstrictor effects of 20-HETE, 20-hydroxyeicosa-6(Z), 15(Z)-dienoic acid (30 mg/kg, s.c.; 1 h 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. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved. |
| Databáze: | OpenAIRE |
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