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Introduction
Stroke, most commonly caused by the interruption of
blood supply to the brain, is one of the leading causes of
disability and mortality in adults. Multiple molecular
mechanisms, including energy crisis, oxidative stress,
calcium overloading, caspase activation, and inflammation have
now been suggested as potential contributors to
ischemia-induced neural injury[1,2]. Unfortunately, there has been no
satisfactory treatment to prevent neural cell death and the
long-term neurological deficits in stroke victims.
In previous studies, we have reported that
prostaglandin A1 (PGA1) inhibited the excitotoxin-induced apoptosis of
striatal neurons in vivo and the rotenone-induced apoptosis
of cultured SH-SY5Y cells in
vitro[3,4]. Lithium has been extensively used in the treatment of bipolar mood disorder,
and recent study has revealed that it is a neuroprotective
drug against a variety of insults, such as glutamate-induced
excitotoxicity[5], ischemia-induced neural damage, and other
neurodegenerative conditions[6_9]. We have found that
PGA1 protects neurons in rodent models of focal
ischemia[10], and the combination of
PGA1 and lithium generates greater neuroprotection under ischemic conditions, possibly through
enhancing the expressions of heat shock protein (HSP)70
and glucose response protein 78
(Grp78)[11].
HSP are a group of stress-induced proteins that act as
molecular chaperones regulating the formation, folding, and
assembly of protein chains and the translocation of
newly-formed proteins[12]. Cerebral ischemia of either focal or
global type enhances the expression of HSP genes and
pro-teins[13_16], which are speculated to be protective proteins.
HSP synthesis is controlled by a family of transcription
factors, the heat-shock factors (HSF). Ischemia and heat
activate HSF-1, which is present in the cytoplasm as an
inac-tive, monomeric form[17]. Trimerization and phosphorylation,
as well as nuclear migration of HSF-1, occur under stress
conditions. HSF-1 binds to the heat-shock element, which is
present in the promoter of the stress response gene and
then initiates HSP transcription and synthesis.
Mammalian HSP90 is one of the most abundant cytosolic
proteins in eukaryotes, amounting to ~1% of soluble
proteins, even in the absence of
stress[18,19]. Previous studies found that HSP90 could form a cytosolic complex with
apoptosis protease activating factor-1 (Apaf-1) and inhibit
cytochrome c-mediated oligomerization of Apaf-1 and the
activation of procaspase-9 acting as an anti-apoptotic
factor[20].
The upregulation of the expression of HSP70 and Grp78
by prostaglandin A1 (PGA1) and lithium (Li) has been
reported[11]. Still, we do not know whether other members of
the HSP family are involved in the neuroprotection of
combined PGA1 and lithium. The present study was undertaken
to explore whether the expressions of other HSP
regulating cell death/survival are affected by
PGA1 and Li. The effect of
PGA1 and Li on Apaf-1, one pro-apoptotic factor
regulated by HSP90, was also examined. The results
indicated that lithium enhanced the effects of
PGA1 on the expressions of HSF-1, heme oxygenase-1 (HO-1),
HSP90α, and HSP90β and downregulated Apaf-1.
Materials and methods
Materials Lithium and PGA1 were purchased from
Sigma-Aldrich Chemical (St Louis, MO, USA).
Rat permanent middle cerebral artery occlusion model
Male Sprague-Dawley rats weighing 280_300 g were
purchased from the Center for Experimental Animals of Soochow
University (Suzhou, China). The National Institutes of Health
(NIH) Guidelines for Care and Use of Laboratory Animals
were followed in all animal procedures. The rats were
anesthetized with an intraperitoneal injection of 4% choral
hydrate (350 mg/kg). Through a ventral midline incision, the
right common carotid artery (CCA), external carotid artery,
and internal carotid artery (ICA) were isolated and ligated. A
30 mm length of monofilament nylon suture (F0.22_0.24 mm),
with its tip rounded by heating near a flame, was inserted
from the right CCA to the ICA through a small incision in the
common carotid artery and then advanced to the Circle of
Willis to occlude the origin of the right middle
cerebral artery. The suture remained there until the rats were
killed[21]. The body temperature of the rats was monitored with a rectal
probe and maintained in the range of 37.0±0.5
oC with a heating pad (BME-412A ANIMAL REGULATOR, 308005669;
Institute of Biomedical Engineering, Hangzhou, Zhejiang,
China) during and after surgery until recovery from
anes-thesia. Sham-operated rats underwent the same procedures,
except for the permanent middle cerebral artery occlusion
(pMCAO). Rats showing tremor and seizure after surgery
were excluded from further experiments. For the study of the
time-course of alterations in the expression of HSF-1, HSP,
and Apaf-1, 15 rats were killed at 1, 2, 3, 6, 12, and 24 h after
ischemic insult (3 rats in each group). For the study of the
effects of PGA1, lithium alone, and a combination of both, 21
rats were divided into 7 groups: sham operated; model;
PGA1 33.3 nmol PGA1(L);
PGA1 16.5 nmol PGA1(S); lithium 1
mEq/kg; PGA1(L)+lithium;
PGA1(S)+lithium.
Lithium and PGA1 treatment For all the experiments, at
the indicated times and doses, lithium was administered
subcutaneously to the rats for 2 d (1 mEq/kg, once a day) and
PGA1 (16.5 or 33 nmol, dissolved in 40% ethanol) was
injected into the lateral cerebro-ventricle once 15 min prior to
the pMCAO. The control animals received the same
quantity of vehicle.
Western blot analysis of HO-1, HSP90α,
HSP90β,
HSF-1, and Apaf-1 Immunoblotting was performed as
previously described[3]. The brain tissues from the ischemic
striatum of the right middle cerebral artery territory and the
corresponding area of the sham-operated rats were rigorously
homogenized; the protein concentrations were determined
using a BCA kit (Pierce, Rockford, IL, USA). An aliquot of 50
µg proteins from each sample was separated using 10%
SDS-PAGE electrophoresis using constant current.
Proteins were subsequently transferred to a nitrocellulose
membrane, which was then incubated with 5% skim milk in
Tris-buffered saline with 0.1% Tween 20 (TBST) at 4 °C
overnight. Afterwards, the membranes were incubated
with the mAb to HSF-1 (1:400; Santa Cruz Biotechnology,
Santa Cruz, CA, USA) at 4 °C for 3 h, then with a horseradish
peroxidase-conjugated anti-mouse secondary antibody
(1:5000; Sigma, USA) at room temperature for 1 h.
Immunoreactivity was detected by enhanced chemiluminescent
autoradiography (Amersham, Princeton, NJ, USA) in
accordance with the manufacturer's instructions. Between each
procedure, the membranes were rinsed 3 times in TBST for
10 min each. The membrane was immediately placed with the
protein side up in the film cassette for exposing. The films
were used for the final determination. The membranes were
reprobed with β-actin (1:5000; Sigma, USA) after striping
(TBST with 2% β-mercaptoethanol at 65 °C for 1 h).
The same method was used to detect HO-1, HSP90α,
HSP90β, and Apaf-1. For the detection of HO-1,
HSP90α, and HSP90β, the first antibodies used to incubate the
membranes were rabbit polyclonal IgG against HO-1 (1:200;
Stressgen Bioreagents, Voctoria, BC, Canada), rat monoclonal
IgG against HSP90α (1:200; Santa Cruz Biotechnology,
USA), rat monoclonal IgG against HSP90β (1:200; Santa
Cruz Biotechnology, USA), and rabbit polyclonal IgG
against Apaf-1 (1:500; Pharmingen, San Jose, CA, USA),
and the second antibody was a horseradish peroxidase-
conjugated anti-rabbit IgG (1:5000; Sigma, USA) and
anti-mouse IgG (1:5000; Sigma, USA).
Statistical analysis Statistical analysis was performed
by one-way ANOVA. P<0.05 was considered to be significant.
Results
Enhanced expression of HSF-1 by combined
PGA1 and lithium The Western blot analysis revealed that the increase
in the levels of HSF-1 in the ischemic striatum was detected
at 12 h and further elevated 24 h after the onset of ischemia.
The levels of HSF-1 were further elevated by pretreatment
with PGA1 (33 nmol) and lithium alone. Moreover, the
combination of lithium and PGA1 (16.5 and 33 nmol, respectively)
elicited a greater increase in HSF-1 levels compared to
PGA1 alone (P<0.05; Figure 1).
Enhanced expression of HO-1 by combined
PGA1 and lithium The elevation of the levels of HO-1 in the ischemic
striatum was detected at 12 h and further increased 24 h after
the onset of ischemia. The increase in the expression of
HO-1 was enhanced by pretreatment with
PGA1 (33 nmol) and lithium alone. The combination of lithium and
PGA1 (16.5 and 33 nmol, respectively), however, induced a greater
increase in HO-1 levels compared to
PGA1 alone (P<0.05; Figure 2).
Enhanced expression of HSP90α by combined
PGA1
and lithium The upregulation of the expression of
HSP90α was detectable at 3 h and was further elevated 24 h after the
onset of ischemia. The levels of HSP90α were even further
increased by pretreatment with PGA1 (33 nmol) and lithium
alone. The combination of lithium and
PGA1 (16.5 and 33 nmol, respectively) elicited a larger rise in
HSP90α levels compared to PGA1 alone
(P<0.05; Figure 3).
Maintenance of HSP90β expression by combined
PGA1 and lithium The downregulation of the expression of
HSP90β in the ischemic striatum was detected at 12 h and further
descended 24 h after the onset of ischemia. However, it was
significantly recovered by pretreatment with
PGA1 (33 nmol) and lithium alone. Moreover, the combination of lithium and
PGA1 (16.5 and 33 nmol, respectively) elicited a greater rise
in HSP90β levels in the ischemic striatum compared to
PGA1 alone (P<0.05; Figure 4).
Inhibition of Apaf-1 expression by combined
PGA1 and lithium The increased expression of Apaf-1 was detected at
6 h and was further elevated 24 h after the onset of ischemia.
Pretreatment with PGA1 (33 nmol) or lithium significantly
inhibited Apaf-1 induction. The combination of lithium and
PGA1 (16.5 and 33 nmol, respectively) further reduced
Apaf-1 levels in the ischemic striatum compared to
PGA1 alone (P<0.05; Figure 5).
Discussion
HSF-1 has been shown to regulate the expression of HSP
in response to ischemia, hypoxia, heat, stress, or
injury[41]. During cerebral ischemia, complex and multiple pathological
events occur within neural cells, such as the loss of high
energy phosphate esters, disturbances in neurotransmitter
metabolism, membrane breakdown, mitochondrial failure, an
accumulation of intracellular Ca2+, and the subsequent
production of oxygen free radicals involving the arachidonic
acid metabolic pathway[42]. Although the detailed
mechanisms remain to be determined, complex pathological events
within ischemic neuronal cells disturb protein metabolism
and break down cellular structures, thus possibly producing
substrates for the molecular chaperones and activating HSF-1.
Conditions that increase the level of oxygen free radicals
have also been reported to induce the stress
proteins[43]. Hypoxia also activates HSF-1 and the
HSF-mediated transcription of HSP70 in myogenic
cells[44]. Mosser et al reported that the concentrations of calcium and hydrogen ions,
which affect protein conformation, directly activate HSF
in vitro[45]. Recent studies have reveled that antiproliferative
prostaglandins also activate HSF, and extracellular exposure
to arachidonic acid activates HSF-1 and heat shock gene
transcription[46,47]. It has been reported recently that cerebral
ischemia or heat shock could activate
HSF-1[48]. Our current findings demonstrate that pMCAO enhanced the expression
of HSF-1 in the ischemic striatum, and pre-ischemic
PGA1 and lithium treatments further enhanced the induction of the
HSF-1 level in the ischemic striatum. This suggests that the
enhanced expression of HSP by
PGA1 and lithium is mediated at the transcriptional level through HSF-1.
HO-1, a HO family member, is a 32 kDa HSP (HSP-32),
which is inducible by a variety of stress factors, including
oxidative stress, exposure to heavy metals, heat, focal
cerebral ischemia, and traumatic brain
injury[22_24]. In the human central nervous system, HO-1 expression was detected in
brain tumors and in neurodegenerative diseases including
Pick's disease, Alzheimer's disease, Parkinson's disease, and
cerebral ischemia[25_27]. It should be noted that the
functional role of HO-1 is still unclear. There are several
indications of the protective function of HO-1. Oxidative stress
has been proposed to be a contributing factor in the
pathophysiology of
ischemia/reperfusion[28]. The products of heme
degradation, bilirubin, and biliverdin were shown to be
protective because of their antioxidant
activity[29,30]. HO-1 was shown to protect vessels against heme and
hemoglobin-mediated injury[31], to protect kidney against
ischemia/perfusion-induced injury[32] and to reduce hyperoxia-induced
lung injury in rats[33]. The increased expression of the HO-1
protein following transient global and permanent focal
ischemia may reflect an elevation of antioxidant defense
mechanisms as a response to ischemia-induced oxidative stress.
In our ischemic model, the HO-1 level was maximally increased
at 24 h post-insult in the ischemic striatum, when the brain
area suffered severe damage after pMACO. Moreover,
pre-ischemic PGA1 and lithium treatments robustly enhanced
the induction of the HO-1 level in the ischemic striatum.
HSP90 is a highly conserved and essential stress protein
for the viability of eukaryotic cells. It is not only abundantly
expressed in cells, but also significantly induced after
stress[34]. In eukaryotes, HSP90 has dual chaperone functions. They
are involved in the conformational maturation of signal
transduction molecules (for example, nuclear hormone receptors
and kinases) and in the cellular stress
response[18]. The finding that HSP90 is induced in response to diverse apoptotic
stimuli, such as UV, sodium arsenite and cerebral ischemia,
has supported its involvement in cell
survival[35_37]. Recently, it was reported that HSP90 could form a cytosolic complex
with Apaf-1 and inhibit cytochrome c-mediated
oligomerization of Apaf-1 and the activation of
procaspase-9[20]. It also could stabilize the receptor-interacting protein, a major
anti-apoptotic adaptor, to activate anti-apoptotic pathways
through NF-κB and mitogen-activated protein kinases
(MAPK)[38]. In addition, Akt is a substrate of HSP90 and
forms a complex with HSP90. The inhibition of Akt_HSP90
binding results in Akt dephosphorylation, a decrease in Akt
kinase activity, and the induction of
apoptosis[39]. In the present study, although
HSP90α expression was enhanced significantly by pMCAO,
HSP90b expression was significantly decreased in the ischemic models. Pre-ischemic
PGA1 and lithium treatment robustly enhanced the induction of
HSP90α levels and maintained the expression of
HSP90β in the ischemic striatum. Our findings in changes in
HSP90β expression is consistent with those reported by Sun
et al, in which HSP90β descended significantly in the
ischemic/reperfusion model, but was maintained by the treatment of
acupuncture[40]. This may contribute to
PGA1 and lithium's protection against cerebral ischemia in our study.
Taken together, pretreatment with
PGA1, lithium, and a combination of both just before cerebral ischemia,
significantly enhanced the expressions of HO-1,
HSP90α, and HSF-1, and maintained HSP90β, but decreased the expression of
Apaf-1 in the ischemic striatum. This is the first
in vivo study showing that pretreatment with
PGA1, lithium, and a combination of both could activate heat shock gene
transcription, suggesting that the combined treatment of
PGA1 and lithium may be considered for the clinical testing
of PGA1 and lithium against ischemic neuronal damage.
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