Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.14.99.3 (heme oxygenase)
4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro and in vivo studies indicate that oxidant stress is implicated in liver fibrogenesis. However, it is still unknown whether, in vivo, oxidant stress directly affects the hepatic cells responsible for fibrogenesis, ie, the hepatic stellate cells (HSCs). This study was aimed at answering this question by assessing the temporal and spatial relationships between oxidant stress and activation of HSCs in an in vivo model of oxidant-stress-associated fibrogenesis. To this purpose, rats were treated with carbon tetrachloride (CCl4) and livers subjected to in situ perfusion with nitroblue tetrazolium, which, in the presence of superoxide ions, is reduced to an insoluble blue-colored formazan derivative and is readily detectable in the tissue by light microscopy. Moreover, various combinations of in situ hybridization and immunocytochemical analyses were performed. An acute dose of CCl4 caused a transient production of superoxide radicals at 24 hours into pericentral necrotic areas, whereas HSC appearance and expression of collagen mRNA were detectable only at 48 and 72 hours. After chronic CCl4 intoxication, higher levels of oxygen radical production in necrotic areas were detectable along with dramatic and sustained activation of HSCs. However, maximal HSC activation was still delayed as compared with superoxide production. Expression of heme oxygenase, a gene responsive to a variety of oxidant stress mediators, was strongly enhanced by chronic CCl4 administration but remained unchanged in HSCs, both in situ and after isolation of pure HSC fractions from control and CCl4-treated animals. In conclusion, during postnecrotic fibrogenesis, oxidant stress anticipates HSC activation. HSCs do not directly face an oxidant stress while engaged in active fibrogenesis.
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PMID:Spatial and temporal dynamics of hepatic stellate cell activation during oxidant-stress-induced fibrogenesis. 958

Oxidant stress plays a key role in hepatic fibrogenesis. This study was undertaken to assess whether, during iron overload-associated liver fibrosis in vivo, oxidant stress occurs in hepatic stellate cells (HSC) during active fibrogenesis. Gerbils were treated with iron-dextran, and, after hepatic fibrosis developed, livers were subjected to various combination of in situ hybridization and immunocytochemistry analyses. In iron-treated animals, no specific accumulation of ferritin protein was found in collagen mRNA-expressing cells. Moreover, the activity of the iron regulatory protein, the main sensor of cellular iron status, was unchanged in HSC from iron-treated animals. Although a significant amount of malondialdehyde-protein adducts was detected in gerbil liver during fibrogenesis, accumulation of these lipid peroxidation by-products was restricted to iron-laden cells adjacent to activated HSC. In cultured gerbil HSC, iron, aldehydes, and other pro-oxidants were able to enhance the expression of an oxidant stress-responsive gene, heme oxygenase (HO), with no change in collagen mRNA accumulation. In keeping with these findings, we found that, in vivo, activation of HO gene was present in iron-filled nonparenchymal cell aggregates, but absent in HSC. In conclusion, the data indicate that during iron overload-associated fibrogenesis, HSC are not directly subjected to oxidant stress, but are likely to be activated by paracrine signals arising in neighboring cells.
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PMID:Hepatic stellate cells are not subjected to oxidant stress during iron-induced fibrogenesis in rodents. 962 Mar 35

The purpose of the study was to investigate interactions between myocardial nitric oxide synthase (NOS) and myocardial fibrosis, both of which determine left ventricular (LV) preload reserve in patients with nonischemic dilated cardiomyopathy (DCM). In previous animal experiments, chronic inhibition of NOS induced myocardial fibrosis and limited LV preload reserve. Twenty-eight DCM patients underwent LV catheterization, balloon caval occlusions (BCO; n = 8), intracoronary substance P infusion (n = 8), and procurement of LV endomyocardial biopsies for determinations of collagen volume fraction (CVF), of gene expression of NOS2, NOS3, heme oxygenase (HO)-1, and TNF-alpha, and of NOS2 protein. CVF was unrelated to the intensity of NOS2, NOS3, HO-1, or TNF-alpha gene expression or of NOS2 protein expression. Preload recruitable LV stroke work (PR-LVSW) correlated directly with NOS2 gene expression (P = 0.001) and inversely with CVF (P = 0.04). High CVF (>10%) reduced baseline LVSW and PR-LVSW at each level of NOS2 gene expression. In DCM, myocardial fibrosis is unrelated to the intensity of myocardial gene expression of NOS, antioxidative enzymes (HO-1), or cytokines (TNF-alpha) and blunts NOS2-related recruitment of LV preload reserve.
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PMID:Myocardial fibrosis blunts nitric oxide synthase-related preload reserve in human dilated cardiomyopathy. 1248 14

Scleroderma, a disease involving excessive collagen deposition, can be studied using fibroblasts cultured from affected tissues. We find that curcumin, the active component of the spice turmeric, causes apoptosis in scleroderma lung fibroblasts (SLF), but not in normal lung fibroblasts (NLF). This effect is likely to be linked to the fact that although curcumin induces the expression of the phase 2 detoxification enzymes heme oxygenase 1 and glutathione S-transferase P1 (GST P1) in NLF, SLF are deficient in these enzymes, particularly after curcumin treatment. The sensitivity of cells to curcumin-induced apoptosis and the expression of GST P1 (but not heme oxygenase 1) are regulated by the epsilon isoform of protein kinase C (PKCepsilon). SLF, which contain less PKCepsilon and less GST P1 than NLF, become less sensitive to curcumin-induced apoptosis and express higher levels of GST P1 when transfected with wild-type PKCepsilon, but not with dominant-negative PKCepsilon. Conversely, NLF become sensitive to curcumin-induced apoptosis and express lower levels of GST P1 when PKCepsilon expression or function is inhibited. The subcellular distribution of PKCepsilon also differs in NLF and SLF. PKCepsilon is predominantly nuclear or perinuclear in NLF but is associated with stress fibers in SLF. Just as PKCepsilon levels are lower in SLF than in NLF in vitro, PKCepsilon expression is decreased in fibrotic lung tissue in vivo. In summary, our results suggest that a signaling pathway involving PKCepsilon and phase 2 detoxification enzymes provides protection against curcumin-induced apoptosis in NLF and is defective in SLF. These observations suggest that curcumin may have therapeutic value in treating scleroderma, just as it has already been shown to protect rats from lung fibrosis induced by a variety of agents.
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PMID:Curcumin-induced apoptosis in scleroderma lung fibroblasts: role of protein kinase cepsilon. 1474 95

Idiopathic pulmonary fibrosis is an incurable fibrosing disorder that progresses relentlessly to respiratory failure. We hypothesized that a product of heme oxygenase activity, carbon monoxide (CO), may have anti-fibrotic effects. To test this hypothesis, mice treated with intratracheal bleomycin were exposed to low-concentration inhaled CO or ambient air. Lungs of mice treated with CO had significantly lower hydroxyproline accumulation than controls. Fibroblast proliferation, thought to play a central role in the progression of fibrosis, was suppressed by in vitro exposure to CO. CO caused increased cellular levels of p21(Cip1) and decreased levels of cyclins A and D. This effect was independent of the observed suppression of MAPK's phosphorylation by CO but was dependent on increased cGMP levels. Further, CO-exposed cells elaborated significantly less fibronectin and collagen-1 than control cells. This same effect was seen in vivo. Suppression of collagen-1 production did not depend on MAPK or guanylate cyclase signaling pathways but did depend on the transcriptional regulator Id1. Taken together, these data suggest that CO exerts an anti-fibrotic effect in the lung, and this effect may be due to suppression of fibroblast proliferation and/or suppression of matrix deposition by fibroblasts.
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PMID:Carbon monoxide suppresses bleomycin-induced lung fibrosis. 1563 97

The objective of the study was to evaluate possible changes of the gene expression and localization of the enzymes, heme oxygenase and nitric oxide synthase (NOS), with reference to increase of collagen type III in response to the partial obstruction of the bladder. Following initial obstruction, whole rat bladders were removed for real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Real-time RT-PCR demonstrated significantly enhanced expression of HO (p < 0.01) and collagen type III (p < 0.001) gene on postoperative day 14. Enhanced expression of NOS gene was seen only on postoperative day 4 (p < 0.01). Immunohistochemistry revealed that immunoreactivity to HO-1 had much in common in neural cells and fibers, although immunoreactivity to HO-2 and iNOS was relatively weak. This study suggested gene expression of HO, especially HO-1, was more dramatically changed than NOS, and was upregulated simultaneously with increase of collagen type III after obstruction. HO systems could be involved in the pathogenesis of bladder dysfunction related to increase of collagen type III after obstruction.
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PMID:Upregulation of heme oxygenase and collagen type III in the rat bladder after partial bladder outlet obstruction. 1740 40

Hypothermia preserves myocardial function, promotes signaling for cell survival, and inhibits apoptotic pathways during 45-min reperfusion. We tested the hypothesis that signaling at the transcriptional level is followed by corresponding proteomic response and maintenance of structural integrity after 3-h reperfusion. Isolated hearts were Langendorff perfused and exposed to mild (I group; n = 6, 34 degrees C) or moderate (H group; n = 6, 30 degrees C) hypothermia during 120-min total ischemia with cardioplegic arrest and 180-min 37 degrees C reperfusion. Moderate hypothermia suppressed anaerobic metabolism during ischemia and significantly diminished left ventricular end-diastolic pressure at the end of ischemia from 52.7 +/- 3.3 (I group) to 1.8 +/- 0.9 (H group) mmHg. Unlike the I group, which showed poor cardiac function and high left ventricular pressure, the H group showed preservation of myocardial function, coronary flow, and oxygen consumption. Compared with normal control hearts without ischemia (n = 5), histological staining in the I group showed marked disarray and fragmentation of collagen network (score 4-5), while the H group showed preserved collagen integrity (score 0-1). The apoptosis-linked tumor suppressor protein p53 was expressed throughout the I group only (score 4-5). The H group produced elevated expression for hypoxia-inducible factor 1alpha and heme oxygenase 1, but minimally affected vascular endothelial growth factor expression. The H group also elevated expression for survival proteins peroxisomal proliferator-activated receptor-beta and Akt-1. These results show in a constant left ventricular volume model that moderate hypothermia (30 degrees C) decreases myocardial energy utilization during ischemia and subsequently promotes expression of proteins involved in cell survival, while inhibiting induction of p53 protein. These data also show that 34 degrees C proffers less protection and loss of myocardial integrity.
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PMID:Moderate hypothermia (30 degrees C) maintains myocardial integrity and modifies response of cell survival proteins after reperfusion. 1766 Apr

Tubulointerstitial fibrosis is a hallmark of chronic progressive kidney disease leading to end-stage renal failure. An endogenous product of heme oxygenase activity, carbon monoxide (CO), has been shown to exert cytoprotection against tissue injury. Here, we explored the effects of exogenous administration of low-dose CO in an in vivo model of renal fibrosis induced by unilateral ureteral obstruction (UUO) and examined whether CO can protect against kidney injury. UUO in mice leads to increased extracellular matrix (ECM) deposition and tubulointerstitial fibrosis within 4 to 7 days. Kidneys of mice exposed to low-dose CO, however, had markedly reduced ECM deposition after UUO. Moreover, low-dose CO treatment inhibited the induction of alpha-smooth muscle actin (alpha-SMA) and major ECM proteins, type 1 collagen and fibronectin, in kidneys after UUO. In contrast, these anti-fibrotic effects of CO treatment were abrogated in mice carrying null mutation of Mkk3, suggesting involvement of the MKK3 signaling pathway in mediating the CO effects. Additionally, in vitro CO exposure markedly inhibited TGF-beta(1)-induced expression of alpha-SMA, collagen, and fibronectin in renal proximal tubular epithelial cells. Our findings suggest that low-dose CO exerts protective effects, via the MKK3 pathway, to inhibit development of renal fibrosis in obstructive nephropathy.
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PMID:Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction. 1809 35

Pro-inflammatory cytokines, matrix metalloproteinases (MMPs) and other catabolic factors participate in the pathogenesis of cartilage damage in osteoarthritis (OA). Pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) mediate cartilage degradation and might be involved in the progression of OA. Previously, we found that haem oxygenase-1 (HO-1) is down-regulated by pro-inflammatory cytokines and up-regulated by IL-10 in OA chondrocytes. The aim of this study was to determine whether HO-1 can modify the catabolic effects of IL-1beta in OA cartilage and chondrocytes. Up-regulation of HO-1 by cobalt protoporphyrin IX significantly reduced glycosaminoglycan degradation elicited by IL-1beta in OA cartilage explants but increased glycosaminoglycan synthesis and the expression of collagen II in OA chondrocytes in primary culture, as determined by radiometric procedures, immunoblotting and immunocytochemistry. HO-1 decreased the activation of extracellular signal-regulated kinase 1/2. This was accompanied by a significant inhibition in MMP activity and expression of collagenases MMP-1 and MMP-13 at the protein and mRNA levels. In addition, HO-1 induction caused a significant increase in the production of insulin-like growth factor-1 and a reduction in the levels of insulin-like growth factor binding protein-3. We have shown in primary culture of chondrocytes and articular explants from OA patients that HO-1 counteracts the catabolic and anti-anabolic effects of IL-1beta. Our data thus suggest that HO-1 may be a factor regulating the degradation and synthesis of extracellular matrix components in OA.
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PMID:Haem oxygenase-1 regulates catabolic and anabolic processes in osteoarthritic chondrocytes. 1820 Jun 30

Fibroblast apoptosis plays a crucial role in normal and pathological scar formation and therefore we studied whether the putative apoptosis-inducing factor curcumin affects fibroblast apoptosis and may function as a novel therapeutic. We show that 25-microM curcumin causes fibroblast apoptosis and that this could be inhibited by co-administration of antioxidants N-acetyl-l-cysteine (NAC), biliverdin or bilirubin, suggesting that reactive oxygen species (ROS) are involved. This is supported by our observation that 25-microM curcumin caused the generation of ROS, which could be completely blocked by addition of NAC or bilirubin. Since biliverdin and bilirubin are downstream products of heme degradation by heme oxygenase (HO), it has been suggested that HO-activity protects against curcumin-induced apoptosis. Interestingly, exposure to curcumin maximally induced HO-1 protein and HO-activity at 10-15 microM, whereas, at a concentration of >20-microM curcumin HO-1-expression and HO-activity was negligible. NAC-mediated inhibition of 25-microM curcumin-induced apoptosis was demonstrated to act in part via restored HO-1-induction, since the rescuing effect of NAC could be reduced by inhibiting HO-activity. Moreover pre-induction of HO-1 using 5-microM curcumin protected fibroblasts against 25-microM curcumin-induced apoptosis. On a functional level, fibroblast-mediated collagen gel contraction, an in vitro wound contraction model, was completely prevented by 25-microM curcumin, while this could be reversed by co-incubation with NAC, an effect that was also partially HO-mediated. In conclusion, curcumin treatment in high doses (>25 microM) may provide a novel way to modulate pathological scar formation through the induction of fibroblast apoptosis, while antioxidants, HO-activity and its effector molecules act as a possible fine-tuning regulator.
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PMID:Curcumin-induced fibroblast apoptosis and in vitro wound contraction are regulated by antioxidants and heme oxygenase: implications for scar formation. 1841 May 27


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