Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study tested the hypothesis that cytochrome P450 (P450) metabolites of arachidonic acid (AA) contribute to the vascular changes in ischemia/reperfusion (I/R) injury in the rat. In this study, P450-dependent omega-hydroxylase-mediated vascular reactivity of the rat renal interlobular and arcuate vessels [preglomerular vessels (PGMV)] was measured in left kidneys subjected to I/R. Clipping the left renal artery and vein for 30 min followed by reperfusion (I/R) for 3, 6, and 24 h markedly reduced renal microsomal omega-hydroxylase-mediated conversion of [(14)C]AA to 20-hydroxyeicosatetraenoic acid (HETE) that amounted to 34, 37, and 58% of the control enzyme activity, respectively. CYP4A protein expression was also reduced. There was no significant change in epoxygenase activity. Despite these changes, constriction of the rat PGMV by AA or endothelin-1 (ET-1) was not different in vessels from the clipped and nonclipped (contralateral) kidney. Clofibrate (250 mg/kg i.p.), an inducer of CYP4A protein and omega-hydroxylase enzymes, did not increase 20-HETE production but selectively enhanced the vasoconstriction produced by AA and ET-1 in the clipped but not the contralateral kidney without affecting the constriction produced by 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F(2alpha). On the other hand, administration of 2% NaCl (w/v, orally for 7 days) to induce P450-dependent epoxygenase activity attenuated AA-induced vasoconstriction but enhanced ET-1-induced vasoconstriction only in the clipped kidney. These data indicate that the reduction in CYP4A protein expression and enzyme activity in I/R is an adaptive mechanism to preserve renal vasculature from excessive vasoconstriction. Moreover, the increase in epoxygenase activity following salt loading may account for the diminished vasoconstriction evoked by AA. However, the enhancing effect of salt on ET-1-induced vasoconstriction in I/R appears to result from an overwhelming effect of salt-induced sensitization of the renal vasculature to ET-1 over the enhanced production of dilator epoxygenase products.
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PMID:Renal cytochrome p450 oxygenases and preglomerular vascular response to arachidonic acid and endothelin-1 following ischemia/reperfusion. 1213 Jul 36

Cytochrome P450s (P450) metabolize arachidonic acid (AA) to hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs). Among these eicosanoids, 20-HETE is formed in a tissue and cell-specific fashion and plays an important role in the regulation of vascular tone in the brain, kidney, heart and splanchnic beds. 20-HETE is a potent vasoconstrictor produced in vascular smooth muscle (VSM) cells. It depolarizes VSM by blocking the open-state probability of Ca2+-activated K+-channels. Inhibitors of the formation of 20-HETE block the myogenic response of renal and cerebral arterioles in vitro and autoregulation of renal and cerebral blood flow in vivo. The formation of 20-HETE in vascular smooth muscle is stimulated by angiotensin II, endothelin and norepinephrine and is inhibited by nitric oxide (NO). 20-HETE also stimulates mitogenic and angiogenic responses in vitro and in vivo. Changes in the production of 20-HETE have been observed in ischemic cerebrovascular diseases, cardiac ischemia-reperfusion injury, kidney diseases, hypertension, diabetes, uremia, toxemia of pregnancy. The physiological and pathophysiological role of 20-HETE in the regulation of vascular tone are being revealed by the use of newly developed inhibitors of the synthesis of 20-HETE and 20-HETE analogs. The present review summarizes recent findings implicating a critical role for 20-HETE in altering cardiovascular function in a variety of pathological conditions.
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PMID:Role of 20-hydroxyeicosatetraenoic acid (20-HETE) in vascular system. 1625 32

Small lipids such as eicosanoids exert diverse and complex functions. In addition to their role in regulating normal kidney function, these lipids also play important roles in the pathogenesis of kidney diseases. Cyclooxygenase (COX)-derived prostanoids play important role in maintaining renal function, body fluid homeostasis, and blood pressure. Renal cortical COX2-derived prostanoids, particularly (PGI2) and PGE2 play critical roles in maintaining blood pressure and renal function in volume contracted states. Renal medullary COX2-derived prostanoids appear to have antihypertensive effect in individuals challenged with a high salt diet. 5-Lipoxygenase (LO)-derived leukotrienes are involved in inflammatory glomerular injury. LO product 12-hydroxyeicosatetraenoic acid (12-HETE) is associated with pathogenesis of hypertension, and may mediate angiotensin II and TGFbeta induced mesengial cell abnormality in diabetic nephropathy. P450 hydroxylase-derived 20-HETE is a potent vasoconstrictor and is involved in the pathogenesis of hypertension. P450 epoxygenase derived epoxyeicosatrienoic acids (EETs) have vasodilator and natriuretic effect. Blockade of EET formation is associated with salt-sensitive hypertension. Ceramide has also been demonstrated to be an important signaling molecule, which is involved in pathogenesis of acute kidney injury caused by ischemia/reperfusion, and toxic insults. Those pathways should provide fruitful targets for intervention in the pharmacologic treatment of renal disease.
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PMID:Physiologic and pathophysiologic roles of lipid mediators in the kidney. 1736 Nov 13

20-HETE, a metabolite of arachidonic acid, has been implicated as a mediator of free radical formation and tissue death following ischemia-reperfusion (IR) injury in the brain and heart. The present study examined the role of this pathway in a simulated IR renal injury model in vitro. Modified self-inactivating lentiviral vectors were generated to stably overexpress murine Cyp4a12 following transduction into LLC-PK(1) cells (LLC-Cyp4a12). We compared the survival of control and transduced LLC-PK(1) cells following 4 h of ATP depletion and 2 h of recovery in serum-free medium. ATP depletion-recovery of LLC-Cyp4a12 cells resulted in a significantly higher LDH release (P < 0.05) compared with LLC-enhanced green fluorescent protein (EGFP) cells. Treatment with the SOD mimetic MnTMPyP (100 microM) resulted in decreased cytotoxicity in LLC-Cyp4a12 cells. The selective 20-HETE inhibitor HET-0016 (10 microM) also inhibited cytotoxicity significantly (P < 0.05) in LLC-Cyp4a12 cells. Dihydroethidium fluorescence showed that superoxide levels were increased to the same degree in LLC-EGFP and LLC-Cyp4a12 cells after ATP depletion-recovery compared with control cells and that this increase was inhibited by MnTMPyP. There was a significant increase (P < 0.05) of caspase-3 cleavage, an effector protease of the apoptotic pathway, in the LLC-Cyp4a12 vs. LLC-EGFP cells (P < 0.05). This was abolished in the presence of HET-0016 (P < 0.05) or MnTMPyP (P < 0.01). These results demonstrate that 20-HETE overexpression can significantly exacerbate the cellular damage that is associated with renal IR injury and that the programmed cell death is mediated by activation of caspase-3 and is partially dependent on enhanced CYP4A generation of free radicals.
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PMID:20-HETE-mediated cytotoxicity and apoptosis in ischemic kidney epithelial cells. 1817 97

Cytochrome P450 (CYP) omega-hydroxylases and their arachidonic acid metabolites play important roles in myocardial ischemia-reperfusion injury. In this study we investigated the effects of several selective CYP omega-hydroxylase inhibitors on myocardial ischemia/reperfusion-induced myocardial apoptosis. Rats were subjected 30 min of ischemia and 2 h of reperfusion. Groups received either 17-octadecynoic acid (17-ODYA, 0.3 or 3 mg/kg), N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS, 0.4 or 0.8 mg/kg), N-hydroxy-N'-(4-butyl-2-methylphenyl) formamidine (HET0016, 0.1 or 1 mg/kg) or vehicle 10 min prior to ischemia. To further assess the role of mitogen-activated protein kinases (MAPKs) in the CYP omega-hydroxylase inhibitor-induced anti-apoptotic effect, rats also received PD98059 (1 mg/kg), SB203580 (1 mg/kg) or SP600125 (6 mg/kg) 15 min prior to ischemia, with subsets of rats also receiving HET0016 10 min prior to ischemia. Compared with vehicle group, 17-ODYA, DDMS and HET0016 significantly inhibited myocardial apoptosis as evidenced by decreased DNA ladder formation, terminal dUTP deoxynucleotidyltransferase nick end-labeling (TUNEL) positive nuclear staining. They also decreased caspase-3 activity and Bax protein expression but up-regulated the expression of Bcl-2. Conversely, exogenous 20-HETE administration exerted opposite effects. Moreover, HET0016 increased the activity of extracellular signal-related protein kinases 1 and 2 (ERK1/2) but had no significant effect on p38 MAPK or c-Jun N-terminal kinase (JNK) during ischemia/reperfusion. Pretreatment with PD98059, the inhibitor of ERK1/2, but not SB203580 or SP600125, almost completely blocked the effect exerted by HET0016. Taken together, these data suggest that CYP omega-hydroxylase inhibition exerts significant anti-apoptosis effects, at least in part, by activation of ERK1/2 in ischemia/reperfusion heart.
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PMID:Cytochrome P450 omega-hydroxylase inhibition reduces cardiomyocyte apoptosis via activation of ERK1/2 signaling in rat myocardial ischemia-reperfusion. 1877 65

Partial exchange transfusion with a cell-free hemoglobin (Hb) polymer during transient middle cerebral artery occlusion (MCAO) reduces infarct volume but fails to increase blood flow, as might be expected with the induced decrease in hematocrit. In ischemic brain, endothelin antagonists are known to produce vasodilation. In nonischemic brain, pial arterioles constrict after Hb exchange transfusion, and the constriction is blocked by an inhibitor of 20-HETE synthesis. We tested the hypothesis that a 20-HETE synthesis inhibitor and an endothelin A receptor antagonist increase pial arteriolar dilation after Hb exchange transfusion during MCAO. Pial arteriolar diameter was measured in the ischemic border region of the distal MCA border region through closed cranial windows in anesthetized rats subjected to the filament model of MCAO. During 2 h of MCAO, pial arteriolar dilation gradually subsided from 37 +/- 3 to 7 +/- 5% (+/-SE). Compared with residual dilation at 2 h of MCAO with vehicle superfusion (14 +/- 3%), loss of dilation was not prevented by superfusion of a 20-HETE synthesis inhibitor (21 +/- 5%), partial Hb exchange transfusion (7 +/- 5%) that decreased hematocrit to 23%, or a combination of the two (5 +/- 5%). However, loss of dilation was prevented by superfusion of an endothelin A receptor antagonist with (35 +/- 4%) or without (32 +/- 5%) Hb transfusion. Pial artery constriction during reperfusion was attenuated by HET0016 alone and by BQ610 with or without Hb transfusion. Systemic administration of the endothelin antagonist during prolonged MCAO increased blood flow in the border region. Thus loss of pial arteriolar dilation in the ischemic border region during prolonged MCAO depends on endothelin A receptor activation, and this effect was independent of the presence of cell-free Hb polymers in the plasma. In contrast to previous work in nonischemic brain, inhibition of oxygen-dependent 20-HETE synthesis does not significantly influence the pial arteriolar response to polymeric Hb exchange transfusion during focal ischemia.
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PMID:Endothelin rather than 20-HETE contributes to loss of pial arteriolar dilation during focal cerebral ischemia with and without polymeric hemoglobin transfusion. 1926 18

20-Hydroxyeicosatetraenoic acid (20-HETE) production is increased in ischemic kidney tissue and may contribute to ischemia/reperfusion (I/R) injury by mediating vasoconstriction and inflammation. To test this hypothesis, uninephrectomized male Lewis rats were exposed to warm ischemia following pretreatment with either an inhibitor of 20-HETE synthesis (HET0016), an antagonist (20-hydroxyeicosa-6(Z),15(Z)-dienoic acid), an agonist (20-hydroxyeicosa-5(Z),14(Z)-dienoic acid), or vehicle via the renal artery and the kidneys were examined 2 days after reperfusion. Pretreatment with either the inhibitor or the antagonist attenuated I/R-induced renal dysfunction as shown by improved creatinine clearance and decreased plasma urea levels, compared to controls. The inhibitor and antagonist also markedly reduced tubular lesion scores, inflammatory cell infiltration, and tubular epithelial cell apoptosis. Administering the antagonist accelerated the recovery of medullary perfusion, as well as renal medullary and cortical re-oxygenation, during the early reperfusion phase. In contrast, the agonist did not improve renal injury and reversed the beneficial effect of the inhibitor. Thus, 20-HETE generation and its action mediated kidney injury due to I/R. Whether or not these effects are clinically important will need to be tested in appropriate human studies.
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PMID:Inhibition of 20-HETE synthesis and action protects the kidney from ischemia/reperfusion injury. 2115 58

Ischemia/reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) that is associated with a patient mortality of up to 50%. Currently there are not effective pharmacologic therapies for AKI. This Commentary highlights recent evidence indicating that 20-HETE plays an important role in IRI and that drugs that target this pathway have potential as therapeutic agents for AKI.
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PMID:20-HETE in acute kidney injury. 2096 39

20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P450 metabolite of arachidonic acid that that contributes to infarct size following focal cerebral ischemia. However, little is known about the role of 20-HETE in global cerebral ischemia or neonatal hypoxia-ischemia (H-I). The present study examined the effects of blockade of the synthesis of 20-HETE with N-hydroxy-N'-(4-n-butyl-2-methylphenyl) formamidine (HET0016) in neonatal piglets after H-I to determine if it protects highly vulnerable striatal neurons. Administration of HET0016 after H-I improved early neurological recovery and protected neurons in putamen after 4 days of recovery. HET0016 had no significant effect on cerebral blood flow. cytochrome P450 4A immunoreactivity was detected in putamen neurons, and direct infusion of 20-HETE in the putamen increased phosphorylation of Na(+), K(+) -ATPase and NMDA receptor NR1 subunit selectively at protein kinase C-sensitive sites but not at protein kinase A-sensitive sites. HET0016 selectively inhibited the H-I induced phosphorylation at these same sites at 3 h of recovery and improved Na(+), K(+) -ATPase activity. At 3 h, HET0016 also suppressed H-I induced extracellular signal-regulated kinase 1/2 activation and protein markers of nitrosative and oxidative stress. Thus, 20-HETE can exert direct effects on key proteins involved in neuronal excitotoxicity in vivo and contributes to neurodegeneration after global cerebral ischemia in immature brain.
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PMID:Attenuation of neonatal ischemic brain damage using a 20-HETE synthesis inhibitor. 2225 Nov 69

20-Hydroxyeicosatetraenoic acid (20-HETE), an arachidonic acid metabolite known to be produced after cerebral ischemia, has been implicated in ischemic and reperfusion injury by mediating vasoconstriction. To develop a positron emission tomography (PET) probe for 20-HETE synthase imaging, which might be useful for monitoring vasoconstrictive processes in patients with brain ischemia, we synthesized a (11)C-labeled specific 20-HETE synthase inhibitor, N'(4-dimethylaminohexyloxy)phenyl imidazole ([(11)C]TROA). Autoradiographic study showed that [(11)C]TROA has high-specific binding in the kidney and liver consistent with the previously reported distribution of 20-HETE synthase. Using transient middle cerebral artery occlusion in rats, PET study showed significant increases in the binding of [(11)C]TROA in the ipsilateral hemisphere of rat brains after 7 and 10 days, which was blocked by co-injection of excess amounts of TROA (10 mg/kg). The increased [(11)C]TROA binding on the ipsilateral side returned to basal levels within 14 days. In addition, quantitative real-time PCR revealed that increased expression of 20-HETE synthase was only shown on the ipsilateral side on day 7. These results indicate that [(11)C]TROA might be a useful PET probe for imaging of 20-HETE synthase in patients with cerebral ischemia.
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PMID:Increase of 20-HETE synthase after brain ischemia in rats revealed by PET study with 11C-labeled 20-HETE synthase-specific inhibitor. 2266 78


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