Abstract-Hypertension is the leading cause of cardiovascular diseases, and angiotensin II is one of the major components of the mechanisms that contribute to the development of hypertension. However, the precise mechanisms for the development of hypertension are unknown. Our recent study showing that angiotensin II-induced vascular smooth muscle cell growth depends on cytochrome P450 1B1 led us to investigate its contribution to hypertension caused by this peptide. Angiotensin II was infused via miniosmotic pump into rats (150 ng/kg per minute) or mice (1000 g/kg per day) for 13 days resulting in increased blood pressure, increased cardiac and vascular hypertrophy, increased vascular reactivity to vasoconstrictor agents, increased vascular reactive oxygen species production, and endothelial dysfunction in both species. The increase in blood pressure and associated pathophysiological changes were minimized by the cytochrome P450 1B1 inhibitor 2,3Ј,4,5Ј-tetramethoxystilbene in both species and was markedly reduced in Cyp1b1 Ϫ/Ϫ mice. These data suggest that cytochrome P450 1B1 contributes to angiotensin II-induced hypertension and associated pathophysiological changes. Moreover, 2,3Ј,4,5Ј-tetramethoxystilbene, which prevents both cytochrome P450 1B1-dependent and -independent components of angiotensin II-induced hypertension and inhibits associated pathophysiological changes could be clinically useful in the treatment of hypertension and associated cardiovascular and inflammatory diseases. (Hypertension. 2010;56:667-674.) Key Words: angiotensin II Ⅲ cytochrome P450 1B1 Ⅲ Cyp1b1 Ϫ/Ϫ mice Ⅲ blood pressure Ⅲ cardiac and vascular hypertrophy Ⅲ vascular reactivity Ⅲ endothelial function A ngiotensin II (Ang II) is a major component of the mechanisms regulating cardiovascular homeostasis by maintaining vascular tone and salt and water balance. 1 Ang II also activates cytosolic phospholipase A 2 and releases arachidonic acid (AA) from phospholipids. 2 AA is metabolized by cyclooxygenase into prostaglandins and thromboxane A 2 , by lipoxygenase into 5-, 12-, and 15-hydroxyeicosatetraenoic acids (HETEs), by cytochrome P450 (CYP) -hydroxylase into 20-HETE, and by epoxygenase into epoxyeicosatrienoic acids. 3 Prostaglandins E 2 and I 2 and epoxyeicosatrienoic acids contribute to antihypertensive mechanisms, 4,5 whereas prostaglandin precursor PGH 2 and 20-HETE contribute to prohypertensive mechanisms. 6 -8 The balance between these antihypertensive and prohypertensive eicosanoids, together with other vasoactive agents, determines blood pressure levels. Products of AA generated via lipoxygenase (12-HETE) or CYP 4A (20-HETE) also promote vascular smooth muscle cell (VSMC) migration, proliferation, or hypertrophy by activating extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK) 9 -13 and contribute to the vasoconstrictor action of Ang II. 14 Moreover, inhibitors of lipoxygenase and CYP 4A minimize Ang II-dependent hypertension. 6,15,16 Ang II and AA also stimulate production of reac...
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 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 gp91phox participate in the protective effect of 5,14-HEDGE against vasodilation, hypotension, tachycardia, and inflammation in the rat model of septic shock.
Sepsis is a systemic inflammatory response syndrome with a suspected or proven infection caused by any pathogen or a clinical syndrome associated with a high probability of infection. The definition of septic shock includes sepsis-induced hypotension despite adequate fluid resuscitation, along with the presence of organ perfusion abnormalities, and ultimately cell dysfunction. As the most common causes of morbidity and mortality in intensive care units worldwide, the societal and economic costs of sepsis and septic shock are staggering. The molecular pathophysiology of sepsis and septic shock and the complex roles played by cytokines, reactive oxygen and nitrogen species, and eicosanoids remain controversal despite decades of study. The lipid A part of lipopolysaccharide, also known as endotoxin, is the most potent microbial mediator of the pathogenesis of sepsis and septic shock. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a vasoconstrictor ω-hydroxylation product of arachidonic acid that is produced by cytochrome P450 (CYP) enzymes, mainly by CYP4A and CYP4F isoforms. Studies from our laboratory and others have provided substantial evidence that administration of a synthetic analog of 20-HETE, N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine, prevents endotox-ininduced vascular hyporeactivity, hypotension, and mortality associated with increased formation of inducible nitric oxide synthase-derived nitric oxide (NO) and cyclooxygenase-2-derived vasodilator prostanoids as well as decreased expression and activity of CYP4A1 and 20-HETE production in a rodent model of septic shock. CYP4A- and CYP4F-derived 20- HETE is also a proinflammatory mediator of endotoxin-induced acute systemic inflammation. In this review, we will present an overview of our current understanding of the interactions between prostanoids, NO, and 20-HETE in sepsis, and provide a rationale for the development of synthetic 20-HETE analogs for the treatment of sepsis and septic shock.
Nitric oxide (NO) produced by inducible NO synthase (iNOS) is responsible for endotoxin (ET)-induced hypotension and vascular hyporeactivity and plays a major contributory role in the multiorgan failure. Endotoxic shock is also associated with an increase in vasodilator prostanoids as well as a decrease in endothelial NO synthase (eNOS) and cytochrome P450 4A protein expression, and production of a vasoconstrictor arachidonic acid product, 20-hydroxyeicosatetraenoic acid (20-HETE). The aim of this study was to investigate the effects of a synthetic analogue of 20-HETE, N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-HEDGE), on the ET-induced changes in eNOS, iNOS and heat shock protein 90 (hsp90) expression as well as 20-HETE and vasodilator prostanoid (6-keto-PGF 1a and PGE 2 ) production. ET-induced fall in blood pressure and rise in heart rate were associated with an increase in iNOS protein expression and a decrease in eNOS protein expression in heart, thoracic aorta, kidney and superior mesenteric artery. ET did not change hsp90 protein expression in the tissues. ET-induced changes in eNOS and iNOS protein expression were associated with increased 6-keto-PGF 1a and PGE 2 levels and a decrease in 20-HETE levels, in the serum and kidney. These effects of ET on the iNOS protein expression and 6-keto-PGF 1a , PGE 2 and 20-HETE levels were prevented by 5,14-HEDGE. Furthermore, a competitive antagonist of vasoconstrictor effects of 20-HETE, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, prevented the effects of 5,14-HEDGE on the ET-induced changes in systemic and renal levels of these prostanoids and 20-HETE. These data are consistent with the view that an increase in systemic and renal 20-HETE levels associated with a decrease in iNOS protein expression and vasodilator prostanoid production contributes to the effect of 5,14-HEDGE to prevent the hypotension during rat endotoxemia.The expression of inducible nitric oxide (NO) synthase (iNOS) is enhanced in many tissues in response to mediators released by ET [1,2]. This leads to increased generation of NO, which contributes to fall in blood pressure, vascular hyporeactivity, multiple organ failure and high mortality rate that are associated with septic shock [2][3][4][5]. Systemic blockade of iNOS opposes the fall in blood pressure in endotoxic shock [2,3,5]. This is not only because of withdrawal of vasodilator effects of NO, but also is associated with increased activity of vasoconstrictor arachidonic acid products including 20-hydroxyeicosatetraenoic acid (20-HETE) [2,6]. In contrast to iNOS, a potential role of the constitutive endothelial cell isoform of NOS (eNOS) in the pathophysiology of endotoxic shock has recently gained controversy because of findings that indicated eNOS as a pro-inflammatory candidate in inflammatory disease conditions [7]. Recent studies not only demonstrate the importance of eNOS for the up-regulation of pro-inflammatory protein expression, but also indicate the autoregulation of NOS expression by NO, as iNOS-derived NO is ...
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