Molecular basis for heme‐dependent induction of heme oxygenase in primary cultures of chick embryo hepatocytes

Srivastava, Kirti; Cable, Edward Earl; Donohue, Susan E.; Bonkovsky, Herbert L.

doi:10.1111/j.1432-1033.1993.tb17835.x

Cited by 45 publications

(26 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been well documented that heme can mediate induction of HO-1 (22,29). This did not appear to be the case in this study because lung heme levels were relatively low in the newly born animals compared with adults, yet they had the highest level of HO activity.…”

Section: Discussionmentioning

confidence: 35%

See 1 more Smart Citation

Developmental Expression of Heme Oxygenase in the Rat Lung

Dennery

2003

Pediatric Research

View full text Add to dashboard Cite

Heme oxygenase (HO), the rate-limiting enzyme in the formation of bilirubin, is expressed in the lung and may serve as an antioxidant. This enzyme results in the formation of antioxidant bile pigments and the degradation of pro-oxidant heme. We wanted to evaluate the differences in expression of HO-1, the inducible form, and HO-2, the constitutive isoenzyme, during lung maturation and document whether lung HO expression was similar to that of other antioxidant enzymes. Lung total HO activity and HO-1 and HO-2 proteins as well as HO-1 and HO-2 mRNA were evaluated in animals from 16 d of gestation (e 16.5 ) to 2 mo of age. Heme content was also evaluated because heme is the substrate of the reaction. HO-1 mRNA was maximal at e 19.5 and e 20.5 , whereas HO-2 mRNA was not changed throughout maturation. Lung HO-1 protein was highest on the first days of life and lowest in adults, whereas HO-2 protein was maximally expressed at postnatal d 5 and then declined to reach adult values. As to HO activity, there was a prenatal peak at e 20.5 , a second lesser peak at d 5, and thereafter a decline to adult values. Lung heme content was inversely correlated with HO activity or protein as the highest heme values were seen in adults with the lowest HO activity. In response to hyperoxia, HO-1 mRNA was induced only in the adult lungs. A better understanding of the maturational regulation of lung HO will define a role for HO in newborns at risk for oxygen toxicity. Abbreviations HO, heme oxygenase e n , day (n) of embryonic life VeCO, excretion of carbon monoxide GAPD, glyceraldehyde-3-phosphate dehydrogenase dCTP, deoxyribocytosine-triphosphate AOE, antioxidant enzyme HO, the rate-limiting enzyme in the degradation of heme and the formation of bilirubin, has been shown to have various roles in antioxidant defense and stress response (1). In particular, HO-1, the inducible form, is up-regulated in hyperoxia (at least in adults) (2) and in other models of oxidative stress (3-6). Neonatal animals do not up-regulate lung HO-1 mRNA in response to hyperoxia (7); however, they are able to increase lung HO-1 mRNA in other circumstances of oxidative stress (8). It is not clear whether HO represents a neonatal antioxidant defense, and it would be important to understand whether the expression of HO parallels that of other antioxidant enzymes in development.HO-2 is the constitutive isoenzyme, which does not get up-regulated in oxidative stress. However, HO-2 has been shown to have important functions in hyperoxia, as hyperoxiaexposed HO-2 knockouts died on average 5 d earlier in hyperoxia than similarly exposed wild-type animals and had a 3-fold increase in serum lipid hydroperoxides indicating increased oxidative stress (9). Therefore, it is also important to evaluate the expression of HO-2 in the lung throughout gestation.There are many examples of AOEs such as catalase, superoxide dismutase, and glutathione peroxidase, which increase in the latter third of gestation (10). It is thought that this increase represents a preparation for the ...

show abstract

Section: Discussionmentioning

confidence: 35%

“…There was also lack of correlation between HO-1 and HO-2 RNA, protein, and (19) and the brain (20) and may reflect the constitutive nature of this enzyme (21) or organ-specific differences in HO-2 regulation. The lack of correlation between HO-1 mRNA and protein may be related to changes in protein or mRNA half-life (22).…”

Section: Discussionmentioning

confidence: 99%

Developmental Expression of Heme Oxygenase in the Rat Lung

Dennery

2003

Pediatric Research

View full text Add to dashboard Cite

show abstract

“…HO has inducible (HO-1) and constitutive (HO-2) isoforms (reviewed in Elbirt & Bonkovsky, 1999). The expression of HO-1 is transcriptionally activated, not only by its substrate heme (Srivastava et al, 1993;Fernandez & Bonkovsky, 1999), but also by a variety of physical and chemical factors, including shear stress, bacterial endotoxins, and cytokines (reviewed in Elbirt & Bonkovsky, 1999). Recently, evidence of a second constitutive isoform (HO-3) has been found (McCoubrey et al, 1997), although its physiological role more likely involves heme binding or heme sensing than heme catabolism, since its specific enzymatic activity is very low.…”

Section: Introductionmentioning

confidence: 99%

Vascular endothelial growth factor increases heme oxygenase‐1 protein expression in the chick embryo chorioallantoic membrane

Fernández

Bonkovsky

2003

British J Pharmacology

View full text Add to dashboard Cite

(1) Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. It has been recently suggested that the inducible heme oxygenase (HO-1) isoform may play a role in angiogenesis. (2) The aims of this study were to determine, in chicken embryo chorioallantoic membranes (CAM), whether VEGF increases HO-1 protein expression, and, if so, by which molecular mechanism, and whether HO-1 activity is required for VEGF-induced angiogenesis. (3) Treatment of CAMs with VEGF for 48 h caused a significant increase in HO-1 protein expression, simultaneously with angiogenesis. (4) VEGF-stimulated angiogenesis in CAMs was markedly attenuated by the HO inhibitor zinc mesoporphyrin (ZnMP). This inhibitory effect of ZnMP was not observed with copper mesoporphyrin (CuMP), a metalloporphyrin that has a similar structure to ZnMP but does not inhibit HO enzymatic activity. (5) Overexpression of HO-1 protein elicited by VEGF in CAMs was significantly attenuated by the intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N\u27,N\u27-tetraacetic acid-acetoxymethyl ester (BAPTA-AM). The effects of BAPTA-AM were, in turn, compensated by the calcium ionophore A-23187. (6) In addition, the protein kinase C inhibitor staurosporine significantly attenuated, in a dose-dependent manner, the VEGF-stimulated HO-1 induction observed in CAMs. (7) These results demonstrate, for the first time, that VEGF upregulates HO-1 protein expression in vivo in CAMs by a mechanism dependent on an increase in cytosolic calcium levels and activation of protein kinase C. Our findings also suggest that HO-1 activity is necessary for VEGF-induced angiogenesis in CAMs

show abstract

“…The results support the concept that zinc mesoporphyrin does not act to directly decrease Alv synthase mRNA, but rather to inhibit heme oxygenase activity and thus increase the size of the regulatory heme pool. Since the cells take up zinc mesoporphyrin as quickly as heme [35], the most logical explanation for the lag-time associated with the zinc-mesoporphyrin-mediated reduction of Alv synthase mRNA is that zinc mesoporphyrin does not act directly to reduce Alv synthase mRNA, but rather inhibits heme oxygenase, which in turn increases the size of a regulatory heme pool, and thereby decreases the level of Alv synthase mRNA.…”

Section: Discussionmentioning

confidence: 99%

“…Such cultures are a simple, reproducible system for exploring hepatic porphyrin metabolism [9,14,21,26,341. We have previously used this culture system to test various metalloporphyrins for their effects on heme metabolism [8,9,35 Methods. Cultures of primary chick embryo liver cells were prepared and chemicals were administered as previously described [8,9,261.…”

mentioning

confidence: 99%

Hepatic 5‐Aminolevulinic Acid Synthase mRNA Stability is Modulated by Inhibitors of Heme Biosynthesis and by Metalloporphyrins

Cable¹,

Gildemeister²,

Pepe³

et al. 1996

European Journal of Biochemistry

Self Cite

View full text Add to dashboard Cite

Hepatic 5-aminolevulinic acid synthase, the first and normally rate-controlling enzyme of heme biosynthesis, is regulated by heme. One of the known mechanisms whereby increased cellular heme regulates 5-aminolevulinic acid synthase is by decreasing the stability of its mRNA. In primary cultures of chick embryo liver cells, we tested whether a decrease in cellular heme might increase 5-aminolevulinic acid synthase mRNA stability and whether heme or other metalloporphyrins could reverse this stabilization. We found that: (a) The stability of 5-aminolevulinic acid synthase inRNA was markedly increased by inhibitors of heme biosynthesis, namely, 4,6-dioxoheptanoic acid or deferoxamine; (b) This increased stability of 5-aminolevulinic acid synthase mRNA was reversed by the addition of heme (10 pM) or by the combination of zinc mesoporphyrin (50 nM), an inhibitor of heme oxygenase, and heme (200 nM); (c) Repression of 5-aminolevulinic acid synthase inRNA levels by zinc mesoporphyrin (10 pM) was due to inhibition of heme oxygenase, rather than a direct, heme-like, effect of zinc mesoporphyrin on 5-aminolevulinic acid synthase mRNA ; (d) Among the several non-heme metalloporphyrins tested, only zinc mesoporphyrin and chromium mesoporphyrin significantly decreased 5-aminolevulinic acid synthase mRNA without increasing heme oxygenase mRNA.

show abstract

Molecular basis for heme‐dependent induction of heme oxygenase in primary cultures of chick embryo hepatocytes

Cited by 45 publications

References 53 publications

Developmental Expression of Heme Oxygenase in the Rat Lung

Developmental Expression of Heme Oxygenase in the Rat Lung

Vascular endothelial growth factor increases heme oxygenase‐1 protein expression in the chick embryo chorioallantoic membrane

Hepatic 5‐Aminolevulinic Acid Synthase mRNA Stability is Modulated by Inhibitors of Heme Biosynthesis and by Metalloporphyrins

Contact Info

Product

Resources

About