Abstract
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, gp91phox (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), gp91phox, p47phox (NOXO2; organizer subunit of gp91phox), and nitrotyrosine (an index for peroxynitrite production) as well as cGMP (an index for sGC activity), 6-keto-PGF1α (a stable metabolite PGI 2) 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 gp91phox participate in the protective effect of 5,14-HEDGE against vasodilation, hypotension, tachycardia, and inflammation in the rat model of septic shock.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 18-41 |
| Number of pages | 24 |
| Journal | Nitric Oxide - Biology and Chemistry |
| Volume | 33 |
| DOIs | |
| State | Published - 2013 |
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Keywords
- COX-2
- CYP4A1
- Endotoxin
- Hypotension
- INOS/sGC/PKG pathway
ASJC Scopus subject areas
- Biochemistry
- Clinical Biochemistry
- Cancer Research
- Physiology
Cite this
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. / Tunctan, Bahar; Korkmaz, Belma; Sari, Ayse Nihal; Kacan, Meltem; Unsal, Demet; Serin, Mehmet Sami; Buharalioglu, C. Kemal; Sahan-Firat, Seyhan; Cuez, Tuba; Schunck, Wolf Hagen; Manthati, Vijaya L.; Falck, John R.; Malik, Kafait U.
In: Nitric Oxide - Biology and Chemistry, Vol. 33, 2013, p. 18-41.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Tunctan, Bahar
AU - Korkmaz, Belma
AU - Sari, Ayse Nihal
AU - Kacan, Meltem
AU - Unsal, Demet
AU - Serin, Mehmet Sami
AU - Buharalioglu, C. Kemal
AU - Sahan-Firat, Seyhan
AU - Cuez, Tuba
AU - Schunck, Wolf Hagen
AU - Manthati, Vijaya L.
AU - Falck, John R.
AU - Malik, Kafait U.
PY - 2013
Y1 - 2013
N2 - 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, gp91phox (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), gp91phox, p47phox (NOXO2; organizer subunit of gp91phox), and nitrotyrosine (an index for peroxynitrite production) as well as cGMP (an index for sGC activity), 6-keto-PGF1α (a stable metabolite PGI 2) 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 gp91phox participate in the protective effect of 5,14-HEDGE against vasodilation, hypotension, tachycardia, and inflammation in the rat model of septic shock.
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, gp91phox (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), gp91phox, p47phox (NOXO2; organizer subunit of gp91phox), and nitrotyrosine (an index for peroxynitrite production) as well as cGMP (an index for sGC activity), 6-keto-PGF1α (a stable metabolite PGI 2) 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 gp91phox participate in the protective effect of 5,14-HEDGE against vasodilation, hypotension, tachycardia, and inflammation in the rat model of septic shock.
KW - COX-2
KW - CYP4A1
KW - Endotoxin
KW - Hypotension
KW - INOS/sGC/PKG pathway
UR - http://www.scopus.com/inward/record.url?scp=84885109307&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84885109307&partnerID=8YFLogxK
U2 - 10.1016/j.niox.2013.05.001
DO - 10.1016/j.niox.2013.05.001
M3 - Article
VL - 33
SP - 18
EP - 41
JO - Nitric Oxide - Biology and Chemistry
JF - Nitric Oxide - Biology and Chemistry
SN - 1089-8603
ER -