Smock
|
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2006 Jan;24(1):16-9. |
[Heme oxygenase-1 expression and
apoptosis induced by cadmium in human embryon kidney
cells]
[Article in Chinese]
Chang XL, Jin TY, Chen L, Dong C.
Department of Occupation Health,
OBJECTIVE: To investigate apoptosis and expression of heme
oxygenase-1 (HO-1) induced by cadmium in human embryonic kidney cells
(HEK239T). METHODS: The MTT method was used for determining the cell
proliferation activity. The apoptosis was determined by the flow cytometry. The HO-l mRNA expression and protein level were
detected by RT-PCR method and Western blot respectively. RESULTS: The ratios of
apoptosis in HEK239T cells were 11.90% +/- 0.28%, 9.27% +/- 1.73%, 9.79% +/-
0.67% and 8 .97% +/- 1.60% at the concentration of 5.0, 10.0, 20.0 and 40.0 micromol/L CdCl(2) respectively,
higher than those in the control group (6.69% +/- 0.46%) with the significant
difference (P < 0.01). The CdCl(2) of between 10 and 40 micromol/L
could highly induce the expression of HO-1 of the human embryonic kidney cells.
The expression would increase slowly till the flat stage with the increase of
the dosage and then would decrease slightly over time. CONCLUSION: The cadmium
can induce the apoptosis of the human embryonic kidney cells and up-regulate
the expression of HO-1.
PMID: 16600087 [PubMed - in process]
|
Biochem Biophys Res Commun. 2006 Apr 14;342(3):984-90. |
Carbon monoxide protects
PC12 cells from peroxynitrite-induced apoptotic death
by preventing the depolarization of mitochondrial transmembrane
potential.
Li MH, Cha YN, Surh
YJ.
Research Institute of Pharmaceutical Sciences,
Heme oxygenase-1 (HO-1), the rate-limiting enzyme in
catalyzing heme degradation into biliverdin,
free iron, and carbon monoxide (CO), serves as a protective enzyme against
oxidative and nitrosative stresses. In the present
study, we investigated the cytoprotective effects of
HO-1 upregulation and its product CO against the peroxynitrite-induced PC12 cell death. PC12 cells treated
with 3-morphoinosydonimine (SIN-1), a generator of peroxynitrite
(ONOO-), underwent apoptotic cell death as evidenced by dissipation of
mitochondrial transmembrane potential (DeltaPsim),
release of mitochondrial cytochrome c into cytoplasm,
cleavage of poly(ADP-ribose)polymerase and
fragmentation of internucleosomal DNA. Pretreatment
of PC12 cells with a low non-toxic concentration of SIN-1 (0.5 mM) induced HO-1 expression and abrogated the cell death
caused by subsequent challenge with high dose SIN-1 (2.5 mM).
Furthermore, pretreatment of PC12 cells with SnCl2, a potent inducer of HO-1
expression, increased endogenous production of CO (HO activity) and rescued the
PC12 cells from peroxynitrite-induced apoptosis. The cytoprotective effect of SnCl2 was abolished when the HO
activity was inhibited by zinc protoporphyrin IX (ZnPP IX). PC12 cells treated directly with the CO-releasing
molecule, tricarbonyldichlororuthenium (II) dimer ([Ru(CO)3Cl2]2) became tolerant to the depolarization of DeltaPsim and apoptosis induced by high dose peroxynitrite. Taken together, these data demonstrate that
the adaptive protection against peroxynitrite-induced
apoptotic death in PC12 cells is mediated by CO formed as a consequence of HO-1
induction.
PMID: 16598857 [PubMed - in process]
|
J Pharmacol Exp Ther. 2006
Mar 24; [Epub ahead of print] |
Induction of heme oxygenase-1 is involved in CO mediated central
cardiovascular regulation.
Lo WC, Lu PJ, Ho WY, Hsiao M, Tseng CJ.
Department of Medical Education and Research,
Carbon monoxide (CO) has been identified as an endogenous biological messenger
in the brain. Heme oxygenase
(HO) catalyzes the metabolism of heme to CO and biliverdin. Previously, we have shown the involvement of CO
in central cardiovascular regulation, baroreflex
modulation, and glutaminergic neurotransmission in
the nucleus tractus solitarii
(NTS) of rats. In this study, we examined which HO isoform
could be induced after hemin injection in the NTS. We
also investigated their in-situ distributions in the NTS after induction. Male
Sprague-Dawley (SD) rats were anesthetized with
urethane, and blood pressure was monitored intra-arterially. Unilateral
microinjection of hemin (1 nmol),
a heme molecule cleaved by HO to yield CO, produced
significant decrease in blood pressure and heart rate. These cardiovascular
effects of hemin were attenuated by prior
administration of HO inhibitor zinc protoporphyrin IX
(ZnPPIX). Microinjection of hemin into NTS resulted
in significant induction of HO-1 protein expression in-situ. Pretreatment of ZnPPIX significantly inhibited the HO-1 induction after hemin injection. No significant changes of HO-2 expressions
were found after hemin injection and ZnPPIX pretreatment. The in-situ inductions of the HO-1
protein expression were further confirmed to be in glial
cells and neurons after hemin injections into the
NTS. These results indicated HO-1 but not HO-2 might be responsible for the
generation of CO and contribute to central control of cardiovascular effects.
|
Toxicol Appl Pharmacol. 2006 Feb 7; [Epub
ahead of print] |
Upregulation of endothelial heme
oxygenase-1 expression through the activation of the JNK pathway by sublethal concentrations of acrolein.
Wu CC, Hsieh CW, Lai PH, Lin JB, Liu YC, Wung
BS.
Acrolein is a highly electrophilic
alpha,beta-unsaturated aldehyde that is present in cigarette smoke. Heme oxygenase-1 (HO-1) is a cytoprotective
enzyme activated by various such electrophilic
compounds. In this study, the regulatory effects of acrolein
upon the expression of HO-1 were investigated in endothelial cells (ECs). We demonstrate that acrolein
induces the elevation of HO-1 protein levels, and subsequent enzyme activity,
at non-cytotoxic concentrations. An additional alpha,beta-unsaturated aldehyde, cinnamaldehyde, was
also found to increase HO-1 expression and have less cytotoxicity
than acrolein. Moreover, acrolein-mediated
HO-1 induction is abrogated in the presence of actinomycin
D and cycloheximide. Nrf2 is a transcription factor
involved in the induction of HO-1 through an antioxidant response element (ARE)
in the promoter region of the HO-1 gene. We show that acrolein
induces Nrf2 translocation and ARE-luciferase
reporter activity. Acrolein was also found to induce
the production of both superoxide and H(2)O(2) at levels greater than 100 muM.
However, with the exception of NAC, no antioxidant generated any effect upon acrolein-dependent HO-1 expression in ECs.
Our present findings suggest that reactive oxygen species (ROS) may not be a
major modulator for HO-1 induction. Using buthionine sulfoximine to deplete the intracellular GSH levels further
enhanced the effects of acrolein. We also found that
cellular GSH level was rapidly reduced after both 10 and 100 muM acrolein treatment. However,
after 6 h of exposure to ECs, only 10 muM acrolein treatment increases
GSH level. In addition, only the JNK inhibitor SP600125 and tyrosine kinase inhibitor genistein had
any significant inhibitory impact upon the upregulation
of HO-1 by acrolein. Pretreatment with a range of
other PI3 kinase inhibitors, including wortmannin and LY294002, showed no effects. Hence, we show
in our current experiments that a sublethal
concentration of acrolein is in fact a novel HO-1
inducer, and we further identify the principal underlying mechanisms involved
in this process.
PMID: 16480751 [PubMed - as supplied by publisher]
|
J Biol Chem. 2006 Apr 4; [Epub
ahead of print] |
Heme oxygenase-1 enhances renal mitochondrial
transport carriers and cytochrome C oxidase activity in experimental diabetes.
Di
Noia MA, Van Driesche S, Palmieri
F, Yang LM, Quan
S, Goodman AI, Abraham NG.
Pharmacology,
Upregulation of heme oxygenase (HO-1) by either cobalt protoporphyrin
(CoPP) or human gene transfer improves vascular and
renal function by several mechanisms, including increases in antioxidant levels
and decreases in reactive oxygen species (ROS) in vascular and renal tissue.
The purpose of the present study was to determine the effect of HO-1 overexpression on mitochondrial transporters, cytochrome c oxidase and
anti-apoptotic proteins in diabetic rats (streptozotocin,
(STZ)-induced type 1). Renal mitochondrial carnitine,
deoxynucleotide and ADP/ATP carriers were
significantly reduced in diabetic compared to nondiabetic
rats (p<0.05). The citrate carrier was not significantly decreased in
diabetic tissue. CoPP administration produced a
robust increase in carnitine, citrate, deoxynucleotide, dicarboxylate
and ADP/ATP carriers but no significant change in oxoglutarate
and aspartate/glutamate carriers. The increase in
mitochondrial carriers (MCs) was associated with a significant increase in cytochrome c oxidase activity.
The administration of tin mesoporphyrin (SnMP), an
inhibitor of HO-1 activity, prevented the restoration of MCs in diabetic rats.
Human HO-1 gene transfer into diabetic rats increased both HO-1 protein and
activity, and restored mitochondrial ADP/ATP and deoxynucleotide
carriers. The increase in HO-1 by CoPP administration
was associated with a significant increase in the phosphorylation
of AKT and levels of BcL-XL proteins. These
observations in experimental diabetes suggest that the cytoprotective
mechanism of HO-1 against oxidative stress involves an increase in the levels
of MCs and anti-apoptotic proteins as well as in cytochrome
c oxidase activity.
PMID: 16595661 [PubMed - as supplied by publisher]
|
J Biol Chem. 2006 Mar 21; [Epub
ahead of print] |
Glycogen synthase kinase-3beta inhibits the xenobiotic
and antioxidant cell response by direct phosphorylation
and nuclear exclusionof the transcription factor
NRF2.
Salazar M, Rojo
AI, Velasco D, de Sagarra
RM, Cuadrado
A.
Dpto.
Bioquimica
and Instituto de Investigaciones
Biomedicas, Universidad
The transcription factor Nrf2 (Nuclear factor E2-related factor 2) regulates
the expression of antioxidant phase II genes and contributes to preserve redox homeostasis and cell viability in response to oxidant
insults. Nrf2 should be coordinated with the canonical cell survival pathway
represented by phosphatidylinositol 3-kinase (PI3K)
and the Ser/Thr kinase Akt but so far the mechanistic connections remain
undefined. Here we identify glycogen synthase
kinase-3beta (GSK-3beta), which is inhibited by Akt-mediated
phosphorylation, as the link between both processes.
Using heme oxygenase-1 (HO-1) as a model phase II
gene, we found that both PI3K and Akt increased mRNA
and protein levels of this enzyme. Pharmacological inhibitors (LiCl and PDZD-8) and genetic variants of GSK-3beta
(constitutively active and dominant negative mutants) indicated that PI3K/Akt
activates and GSK-3beta inhibits the Antioxidant Response Elements of the ho1
promoter and pointed Nrf2 as directly involved in this process. Indeed,
GSK-3beta phosphorylated Nrf2 in vitro and in vivo. Immunocytochemistry and subcellular
fractionation analyses demonstrated that the effect of GSK-3beta-mediated phosphorylation of Nrf2 is to exclude this transcription
factor from the nucleus. Nrf2 up-regulated the expression of HO-1, glutathione peroxidase, glutathione S transferase
A1, NAD(P)H: quinone oxidoreductase
and glutamate-cysteine ligase
and protected against hydrogen peroxide-induced glutathione depletion and cell
death, while co-expression of active GSK-3beta attenuated both phase II gene
expression and oxidant protection. These results contribute to clarify the
crosstalk between the survival signal elicited by PI3K/Akt and the antioxidant
phase II cell response, and introduce GSK-3beta as the key mediator of this
regulation mechanism.
PMID: 16551619 [PubMed - as supplied by publisher]
|
Free
Radic Biol Med. 2006
Apr 1;40(7):1250-63. Epub
2005 Dec 19. |
Effect
of heme and heme
oxygenase-1 on vascular endothelial growth factor synthesis and angiogenic potency of human keratinocytes.
Jazwa
A, Loboda
A, Golda S, Cisowski
J, Szelag
M, Zagorska
A, Sroczynska
P, Drukala
J, Jozkowicz
A, Dulak
J.
Department of Medical Biotechnology, Faculty of Biotechnology, Jagiellonian University, Gronostajowa
7, 30-387 Krakow, Poland.
BACKGROUND: Skin injury leads to the release of heme,
a potent prooxidant which is degraded by heme oxygenase-1 (HO-1) to carbon monoxide, iron, and biliverdin, subsequently reduced to bilirubin.
Recently the involvement of HO-1 in angiogenesis has been shown; however, the
role of heme and HO-1 in wound healing angiogenesis
has not been yet investigated. RESULTS: Treatment of HaCaT
keratinocytes with hemin (heme chloride) induced HO-1 expression and activity. The
effect of heme on vascular endothelial growth factor
(VEGF) synthesis is variable: induction is significant after a short, 6 h
treatment with heme, while longer stimulation may
attenuate its production. The involvement of HO-1 in VEGF synthesis was
confirmed by inhibition of VEGF expression by SnPPIX,
a blocker of HO activity and by attenuation of HO-1 mRNA expression with
specific siRNA. Importantly, induction of HO-1 by hemin was able to overcome the inhibitory effect of high
glucose on VEGF synthesis. Moreover, HO-1 expression was also induced in keratinocytes cultured in hypoxia, with concomitant
augmentation of VEGF production, which was further potentiated
by hemin stimulation. Accordingly, conditioned media
from keratinocytes overexpressing
HO-1 enhanced endothelial cell proliferation and augmented formation of
capillaries in angiogenic assay in vitro.
CONCLUSIONS: HO-1 is involved in hemin-induced VEGF
expression in HaCaT and may play a role in hypoxic
regulation of this protein. HO-1 overexpression may
be beneficial in restoring the proper synthesis of VEGF disturbed in diabetic
conditions.
|
J Hepatol. 2006 Feb 3; [Epub
ahead of print] |
HCV proteins increase
expression of heme oxygenase-1 (HO-1) and decrease
expression of Bach1 in human hepatoma cells.
Ghaziani
T, Shan Y, Lambrecht
RW, Donohue SE, Pietschmann
T, Bartenschlager
R, Bonkovsky
HL.
Department of Medicine, University of Connecticut Health Center, 263 Farmington
Avenue, Farmington, CT 06030-1111, USA; The Liver-Biliary-Pancreatic
Center, University of Connecticut Health Center, 263 Farmington Avenue,
Farmington, CT 06030-1111, USA.
BACKGROUND/AIMS: Hepatitis C infection induces hepatic oxidative stress. Heme oxygenase (HO), the rate-controlling
enzyme of heme catabolism, plays a key role as a protectant against oxidative, and
other stresses. Other recent work has implicated Bach1, a heme
binding protein that represses gene expression, in the regulation of HO-1 gene
expression. METHODS: We investigated the effects of HCV polyprotein
expression on expression of HO-1 and Bach1 genes in human hepatoma
cells (Huh-7 cells). RESULTS: HO-1 was up-regulated in the cell line expressing
HCV proteins from core up to the aminoterminal domain
of NS3. Addition of increasing concentrations of N-acetylcysteine
(NAC) led to down-regulation of HO-1 in cells expressing HCV proteins. In
contrast, Bach1 was significantly down-regulated in these cells. Sodium arsenite, a strong inducer of oxidative stress and HO-1,
reduced Bach1 expression in wild type Huh-7 cells, and NAC partially abrogated
this decrease. CONCLUSIONS: Huh-7 cells expressing HCV proteins show
significant up-regulation of the HO-1 gene, and reciprocal down-regulation of
the Bach1 gene. Exogenous oxidative stressors and anti-oxidants can modulate
expression of these genes. These and other results suggest a key role of
down-regulation of Bach1 and up-regulation of HO-1 in diminishing cytotoxic effects of HCV proteins in human hepatocytes.
PMID: 16530877 [PubMed - as supplied by publisher]
|
J Hepatol. 2006 Feb 6; [Epub
ahead of print] |
Regulation
of rat heme oxygenase-1 expression by interleukin-6
via the Jak/STAT pathway in hepatocytes.
Tron
K, Samoylenko
A, Musikowski
G, Kobe F, Immenschuh
S, Schaper
F, Ramadori
G, Kietzmann
T.
Abteilung Gastroenterologie und Endokrinologie,
Uniklinikum, Georg-August-Universitat
Gottingen, D-37075 Gottingen,
Germany.
BACKGROUND/AIMS: Heme oxygenase-1 (HO-1) can be
induced by various stimuli, one of which is interleukin-6 (IL-6). Therefore, it
the aim of this study was to elucidate the molecular mechanisms responsible for
IL-6-dependent HO-1 induction in the liver. METHODS: The IL-6-dependent HO-1
regulation in rat primary hepatocytes and HepG2 hepatoma cells was studied by Northern and Western blot
analyses, HO-1 promoter reporter gene assays and EMSA. RESULTS: The HO-1
expression was transcriptionally induced by IL-6 in a
time- and dose-dependent manner. Activation of signal transducers and
activators of transcription (STAT) factors by the IL-6 receptor was crucial for
HO-1 induction. By contrast, negative regulation of HO-1 expression appeared to
be mediated through the SH2-domain-containing tyrosine phosphatase-2 (SHP2)/
suppressors of cytokine signaling-3 (SOCS3) binding site within the gp130 IL-6
receptor subunit. Among the three putative STAT binding elements (SBE) in the
HO-1 promoter, only the distal one was functional and when deleted, the
remaining Luc induction was completely obliterated by the phosphatidylinositol
3-kinase (PI3K) inhibitor LY294002. CONCLUSIONS: The HO-1 SBE3 mediates HO-1
gene induction by IL-6 mainly via activation of the Jak/STAT
pathway.
PMID: 16510205 [PubMed - as supplied by publisher]
|
Cell
Death Differ. 2006 Feb 17; [Epub ahead of
print] |
Flunarizine induces Nrf2-mediated transcriptional
activation of heme oxygenase-1 in protection of
auditory cells from cisplatin.
So HS, Kim HJ, Lee JH, Lee JH, Park SY, Park C, Kim YH, Kim JK, Lee KM, Kim KS, Chung SY, Jang WC, Moon SK, Chung HT, Park RK.
1Vestibulocochlear Research Center & Department of Microbiology, Wonkwang University School of Medicine, Jeonbuk
570-749, Korea.
We investigated the cytoprotective mechanisms of flunarizine in cisplatin-induced
death of auditory cells. Concomitant with an increase in viability, treatment
with flunarizine resulted in a marked dissociation of
Nrf2/Keap1 and subsequent intranuclear translocation
of Nrf2, which was mediated by PI3K-Akt signaling. Overexpression
of Nrf2 protected cells from cisplatin along with
transcriptional activation of ARE to generate heme
oxygenase-1 (HO-1). Pretreatment with flunarizine
predominantly increased the transcriptional activity of HO-1 among Nrf2-driven
transcripts, including HO-1, NQO1, GCLC, GCLM, GSTmu-1, and GSTA4. Furthermore,
both pharmacological inhibition and siRNA transfection of HO-1 completely abolished the flunarizine-mediated protection of HEI-OC1 cells and the
primary rat (P2) organ of Corti explants from cisplatin. These results suggest that Nrf2-driven
transcriptional activation of ARE through PI3K-Akt signaling augments the
generation of HO-1, which may be a critically important determinant in cellular
response toward cisplatin and the cytoprotective
effect of flunarizine against cisplatin.Cell
Death and Differentiation advance online publication, 17 February 2006;
doi:10.1038/sj.cdd.4401863.