Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biological significance of the heme oxygenase (HO) system's response to stress reflects functions of its products-CO and bile pigments. CO is a messenger molecule, whereas bile pigments are antioxidants and modulators of cell signaling. Presently, an unexpected mechanism for sustained suprainduction of renal HO-1 following ischemia/reperfusion injury is described. Inhibition of nitric-oxide synthase (NOS) activity by Nomega-nitro-l-arginine methyl ester (l-NAME) at the resumption of reperfusion of rat kidney subjected to bilateral ischemia (30 min) was as effective as the most potent HO-1 inducer, the spin trap agent n-tert-butyl-alpha-phenyl nitrone (PBN), in causing sustained suprainduction of HO-1 mRNA. PBN forms stable radicals of oxygen and nitrogen. Twenty-four hours after reperfusion, HO-1 mRNA measured approximately 30-fold that of the control in the presence of l-NAME treatment; in its absence, the transcript increased to only approximately 5-fold. At 4 h in the presence or absence of the l-NAME HO-1, mRNA was increased by approximately 30-fold. The transcript was translated to active protein as indicated by Western blotting, immunohistochemistry, and activity analyses. l-NAME was not effective given 1 h after resumption of reperfusion. Suprainduction was restricted to the kidney and not detected in the heart and aorta; ferritin expression in the kidney was not effected. It is reasoned that in tissue directly insulted by ischemia/reperfusion, increased production of NO radicals promotes the loss of HO-1 transcript. Because the absence of NO radicals and presence of PBN had a similar effect on HO-1, we propose that suprainduction of the gene is mainly caused by O2 radicals formed on reperfusion. Inhibition of NOS is potentially useful for sustained induction of HO-1 in organs that will be subjected to oxidative-stress insult.
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PMID:Nitric oxide inhibitor N omega -nitro-l-arginine methyl ester potentiates induction of heme oxygenase-1 in kidney ischemia/reperfusion model: a novel mechanism for regulation of the oxygenase. 1267 88

Platelet-derived growth factor (PDGF) is a multifunctional protein which is known to induce a febrile response when injected intracerebroventricularly. The gaseous neurotransmitters, nitric oxide (NO) and carbon monoxide (CO), are both known to exert thermoregulatory effects and to participate in lipopolysaccharide-induced fever. In this study, we investigated the role of NO and CO in the febrile response to PDGF-BB in rats. Intracerebroventricular (i.c.v.) injection of PDGF-BB produced a dose-dependent increase in body temperature. This increase in body temperature induced by PDGF-BB was exacerbated by N(G)-nitro-L-arginine methyl ester (L-NAME-a nonselective NO synthase inhibitor) and S-methyl-L-thiocitrulline treatment [SMTC-a neuronal NOS (nNOS) selective inhibitor], but not by aminoguanidine treatment [an inducible NOS (iNOS) selective inhibitor]. Zinc deuteroporphyrin 2,4-bis glycol treatment (ZnDPBG-a nonselective heme oxygenase (HO) blocker) did not affect PDGF-BB fever. Our data indicate that the NO but not the CO pathway participates in PDGF-BB fever. Furthermore, our data show that nNOS is the NOS isoform responsible for NO synthesis in this response.
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PMID:Fever induced by platelet-derived growth factor, in contrast to fever induced by lipopolysaccharide, depends only on nitric oxide, but not on carbon monoxide pathway. 1270 66

We studied the effects of the heme oxygenase (HO) inhibitor stannous mesoporphyrin (SnMP; 40 micromol/kg i.v.) on renal hemodynamics in anesthetized rats with and without 48-h pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis. SnMP decreased renal blood flow (RBF) and increased renal vascular resistance (RVR) in both groups. The SnMP-induced reduction of RBF in L-NAME-pretreated rats was more prominent than in rats without pretreatment (43 +/- 7 vs. 13 +/- 3%) as was the SnMP-induced elevation of RVR (87 +/- 31 vs. 14 +/- 5%). The renal vasoconstrictor effect of SnMP is linked, in part, to amplification of prevailing neurohormonal constrictor mechanisms, since in L-NAME-pretreated rats it was prevented by concurrent administration of prazosin or losartan. However, SnMP (15 micromol/l) also elicits vasoconstriction in isolated, pressurized renal interlobular arteries and the response is more intense in vessels obtained from L-NAME-pretreated rats than from rats without pretreatment. These data indicate that the status of NO synthesis conditions the vascular response to HO inhibition in the rat kidney.
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PMID:Nitric oxide synthesis influences the renal vascular response to heme oxygenase inhibition. 1273 67

Aspirin is known to exert antioxidant effects by as yet unidentified mechanisms. In cultured endothelial cells derived from human umbilical vein, aspirin (30-300 microM) increased heme oxygenase-1 (HO-1) protein levels in a concentration-dependent fashion up to fivefold over basal levels. HO-1 induction was accompanied by a marked increase in catalytic activity of the enzyme as reflected by enhanced formation of both carbon monoxide and bilirubin. Pretreatment with aspirin or bilirubin at low micromolar concentrations protected endothelial cells from hydrogen peroxide-mediated toxicity. HO-1 induction and endothelial protection by aspirin were not mimicked by indomethacin, another inhibitor of cyclooxygenase. The nitric oxide (NO) synthase blocker L-NAME prevented aspirin-dependent HO-1 induction. These findings demonstrate that aspirin targets HO-1, presumably via NO-dependent pathways. Induction of HO-1 expression and activity may be a novel mechanism by which aspirin prevents cellular injury under inflammatory conditions and in cardiovascular disease.
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PMID:Heme oxygenase-1 induction may explain the antioxidant profile of aspirin. 1292 12

It has recently been reported that not only endogenous nitric oxide (NO) but also carbon monoxide (CO) produced by heme oxygenase (HO) have many physiological functions. The objective of the present study was to determine whether endogenous NO or CO is involved in the experimental pulmonary or liver metastasis of colon cancer in mice. Intravenous or intrasplenic injection of colon 26 cells from a mouse colon adenocarcinoma cell line resulted in multiple pulmonary or liver metastases. NG-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NO synthase (NOS), or zinc deuteroporphyrin 2, 4-bis glycol (ZnDPBG), a competitive inhibitor of HO, was administered to the mice only on the day of tumor inoculation. We assessed the number of tumor cells 24 h later and the outcome of metastases of the target organ. In the pulmonary metastasis model, L-NAME increased both the number of tumor cells 24 h later and outcome of metastases 18 days later, but did not have a significant effect on liver metastasis. On the other hand, metastasis to the liver, but not that to the lung, increased following administration of ZnDPBG. These results suggest that the activities of NOS and HO could influence experimental metastasis in an organ-specific manner.
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PMID:Different effects of constitutive nitric oxide synthase and heme oxygenase on pulmonary or liver metastasis of colon cancer in mice. 1452 34

The aim of the study was to investigate the interaction between nitric oxygenase (NOS)/nitric oxide (NO) and heme oxygenase (HO)/carbon monoxide (CO) system in the pathogenesis of recurrent febrile seizures (FS). On a rat model of recurrent FS, the ultrastructure of hippocampal neurons was observed under electron microscopy, and expression of neuronal NOS (nNOS) in hippocampus and NO formation in plasma were examined after treatment with ZnPP-IX, an HO-1 inhibitor. In the ultrastructure of hippocampal neurons, the expression of HO-1 in hippocampus and CO formation in plasma were examined after treatment with L-NAME, a NOS inhibitor. We found that hippocampal neurons were injured after recurrent FS. The gene and protein expression of nNOS and HO-1 increased markedly in hippocampus in FS rats, while CO formation in plasma increased markedly and the concentration of NO in plasma increased slightly. ZnPP-IX could worsen the neuronal damage of recurrent FS rats. However, it further increased the expression of nNOS and endogenous production of NO obviously. L-NAME alleviated the neuronal damage of recurrent FS rats, but decreased the expression of HO-1 and CO formation. The results of this study suggested that endogenous NOS/NO and HO/CO systems might interact with each other and therefore play an important regulating role in recurrent FS brain damage.
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PMID:Interaction between endogenous nitric oxide and carbon monoxide in the pathogenesis of recurrent febrile seizures. 1476 14

The effects of heme oxygenase (HO) inhibitors, zinc-protoporphyrin-IX (ZnPP-IX), and tin protoporphyrin-IX (SnPP-IX) and their interactions with L-arginine/nitric oxide synthase (NOS) and cyclooxygenase (COX) pathways were investigated in postoperative ileus in rats. Intestinal transit was measured as Evans blue migration after skin incision, laparotomy or laparotomy plus gut evisceration and handling. Laparotomy and small intestinal manipulations increased blood plasma nitrites/nitrates level 1.88-fold. N(omega)-nitro-L-arginine methyl ester, indomethacin, a selective COX-1 blocker (resveratrol) and COX-2 antagonists (nimesulide, DuP-697, NS-398) reversed the additional inhibitory effects of gut manipulation subsequent to laparotomy. In contrast, N-(3-(aminomethyl)benzyl)acetamidine or S-methylisothiourea, highly selective inducible NOS blockers, remained ineffective. ZnPP-IX and SnPP-IX overturned the effects of laparotomy on dye propulsion, but were only partially effective after laparotomy and gut handling attenuating the additional inhibitory influences of gut manipulation, the intestinal transit reaching 89.21%, 92.87%, 53.46%, and 48.56% of respective controls transit. Salutary effects of L-NAME, ZnPP-IX, and SnPP-IX were dose-dependent, L-arginine or hemin (HO substrate) sensitive. Administration of indomethacin and resveratrol subsequent to SnPP-IX reversed the inhibitory effects of laparotomy and manipulation, amounting to 93.91% and 87.43% of controls. On the other hand, L-NAME injected after SnPP-IX abolished the salutary effects of the latter, study dye migration reached 25.18% of control rat. Therefore we demonstrated that nitric oxide, carbon monoxide, and prostanoids play a role in the pathogenesis of postoperative ileus albeit in different mechanisms. Laparotomy stimulated HO activity, whereas gut manipulation led to an excessive constitutive NOS stimulation accompanied by augmented prostanoid synthesis by COX-1. Unaffected synthesis of either NO or CO enables a return of gastrointestinal transit during postoperative period, whereas a pharmacological blockade of two complementary metabolic pathways provides a most effective measure against postoperative ileus development.
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PMID:The role and interactions of nitric oxide (NO), carbon monoxide (CO), and prostanoids in the pathogenesis of postoperative ileus in rats. 1501 33

The purpose of this study was to test specific mechanisms of protection afforded the rat extensor digitorum longus (EDL) muscle during ischemic tolerance. Two days following five cycles of 10 min ischemia and 10 min reperfusion, heme oxygenase (HO) and calcium-dependent nitric oxide synthase (cNOS) activities were increased 2- and 2.5-fold (p <.05), respectively. Interestingly, calcium-independent NOS (iNOS) activity was completely downregulated (p <.05). The levels of superoxide dismutase (SOD) and catalase were increased 2-fold (p <.05), while glutathione peroxidase activity remained unchanged from non-preconditioned controls. Using intravital microscopy combined with chromium mesoporphyrin (CrMP), a selective HO inhibitor, and l-NAME, a NOS inhibitor, the roles of HO and cNOS were evaluated. Ischemic tolerance in the EDL muscle, 48 h after the preconditioning stimulus, was characterized by complete protection from both microvascular perfusion deficits and tissue injury after a 2-h period of ischemia. Removal of NOS activity completely removed the benefit afforded microvascular perfusion, while inhibition of HO activity prevented the parenchymal protection. These data suggest that ischemic tolerance within skeletal muscle is associated with the upregulation of specific cytoprotective proteins and that the benefits afforded by cNOS and HO activity are spatially discrete to the microvasculature and parenchyma, respectively.
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PMID:Protective mechanisms during ischemic tolerance in skeletal muscle. 1503 56

1. Portal hypertension (PH), a major syndrome in cirrhosis, producing hyperdynamic splanchnic circulation and hyperaemia. In order to elucidate the contribution of heme oxygenase to the vascular hyporeactivity, we assessed the activity of heme oxygenase-1 (HO-1), measured the in vivo pressure response to noradrenaline (NA) and investigated the effects of blocking the carbon monoxide (CO) and nitric oxide (NO) pathways in a prehepatic model of PH in rats. 2. Portal hypertension was induced by partial portal vein ligation (PPVL). Noradrenaline was injected intravenously. Liver, spleen and mesentery homogenates were prepared for measurement of HO-1 activity and expression. Four groups of rats were used: (i) a sham group; (ii) a PPVL group; (iii) a sham group pretreated with Zn-protoporphyrin IX (ZnPPIX); and (iv) a PPVL group pretreated with ZnPPIX. Each group was studied before and after treatment with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). 3. For basal pressures and the pressure response to NA, inhibition of CO and NO pathways by ZnPPIX and L-NAME, respectively, produced an increase in mean arterial pressure (MAP) in sham-operated and in PH rats. Similarly, when both inhibitors were used together in either sham or PPVL rats, a greater increase in MAP was observed. 4. These results, together with the increased HO-1 activity and expression only in the PH group, have led us to suggest that the heme oxygenase/CO pathway is involved in the vascular response to NA in PH rats.
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PMID:Role of heme oxygenase/carbon monoxide pathway on the vascular response to noradrenaline in portal hypertensive rats. 1574 3

Oxidative damage to the vascular endothelial cells may play a crucial role in mediating glucose-induced cellular dysfunction in chronic diabetic complications. The present study was aimed at elucidating the role of glucose-induced alteration of highly inducible heme oxygenase (HO) in mediating oxidative stress in the vascular endothelial cells. We have also investigated the interaction between HO and the nitric oxide (NO) system, and its possible role in alteration of other vasoactive factors. Human umbilical vein endothelial cells (HUVECs) were exposed to low (5mmol/l) and high (25mmol/l) glucose levels. In order to determine the role of HO in endothelial dysfunction and to elucidate a possible interaction between the HO and NO systems, cells were exposed to HO inducer (hemin, 10 micromol/l), HO antagonist (SnPPIX, 10 micromol/l), and NO synthase blocker (L-NAME, 200 micromol/l) with or without NO donor (arginine, 1 mmol/l). mRNA expression of HO and NO isoforms was measured by real time RT-PCR. HO activity was measured by bilirubin production and cellular oxidative stress was assessed by 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nitrotyrosine staining. We also determined the expression of vasoactive factors, endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF). In the endothelial cells, glucose caused upregulation of HO-1 expression and increased HO activity. A co-stimulatory relationship between HO and NO was observed. Increased HO activity also associated with oxidative DNA and protein damage in the endothelial cells. Furthermore, increased HO activity augmented mRNA expression of vasoactive factors, ET-1 and VEGF. These data suggest that HO by itself and via elaboration of other vasoactive factors may cause endothelial injury and functional alteration. These findings are of importance in the context of chronic diabetic complications.
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PMID:Pro-oxidant role of heme oxygenase in mediating glucose-induced endothelial cell damage. 1576 54


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