Hypoxia tolerance in mammalian heterotherms
1 Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK
99775, USA
2 Department of Neurology, Case Western Reserve University, Cleveland, OH
44106, USA
3 Institute of Pathology, Case Western Reserve University, Cleveland, OH
44106, USA
* Author for correspondence (e-mail: ffkld{at}uaf.edu)
Accepted 26 May 2004
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Summary |
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Key words: hibernation, ischemia, JNK/SAPK, inflammation, reoxygenation, hypothermia, antioxidant defense, metabolic suppression
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Introduction |
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Attenuation of the cytotoxic cascade in hibernating animals |
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Exhaustion of energy stores rapidly leads to loss of ion homeostasis,
causing an influx of Na+ and Cl ions, edema,
neuronal depolarization, release of neurotransmitters and opening of
voltage-gated ion channels including voltage-gated Ca2+ channels.
Increases in concentration of glutamate in the extracellular space further
stimulate Ca2+ influx into neurons. Subsequent generation of
reactive oxygen species (ROS), as well as other events, leads to both necrotic
and apoptotic processes (Dirnagl et al.,
1999). In addition, activation and nuclear translocation of
stress-activated protein kinases, nuclear factor
B (NF-
B) and
other transcription factors initiate a pro-inflammatory reaction. Intervention
at any point of the cytotoxic cascade has the potential to minimize
neurological deficit (Fig.
1).
|
Evidence suggests that adaptations in heterothermic mammals attenuate the
cytotoxic cascade at multiple levels (Drew
et al., 2001) and differ in many respects from the classic
mechanisms of anoxia tolerance in turtles and fish. Heterothermic animals do
not have the same glycolytic capacity described for anoxia-tolerant turtles
and fish (Lutz and Nilsson,
1997
; Perez-Pinzon et al.,
1997
; Jackson,
2002
). Indeed, one aspect of hibernation is a shift from
carbohydrate to lipid metabolism (Buck et
al., 2002
), and hibernation is often associated with a decrease in
plasma glucose concentrations (Osborne et
al., 1999
). Moreover, while heterothermic mammals have an immense
capacity to lower body temperature and decrease oxygen demand, especially when
hibernating, hypoxia or anoxia does not induce the same degree of hypothermia
and metabolic suppression in ground squirrels as it does in hypoxia-tolerant
turtles and fish (Bullard et al.,
1960
). Additional adaptations in heterothermic mammals may
synergize with hypothermia and metabolic suppression to attenuate the
cytotoxic cascade. Because many of these protective mechanisms such as
hypothermia, metabolic suppression, immunosuppression/leukocytopenia and
increased antioxidant defenses differ between hibernating (torpid) and
euthermic animals, we will discuss hypoxia tolerance in hibernating animals
separately from hypoxia tolerance in euthermic animals
(Fig. 1; reviewed in
Drew et al., 2001
).
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Hypoxia tolerance in the hibernating state: evidence and mechanisms |
---|
Interestingly, many hibernating species in steady-state torpor are
not hypoxic despite 10-fold or greater decreases in respiratory
rates. During torpor, Arctic ground squirrels (Spermophilus parryii),
as well as other species of ground squirrel, are well oxygenated with normal
to above normal arterial oxygen pressures
(Frerichs et al., 1994; Y. L.
Ma, X. Zhu, P. M. Rivera, O. Toien, B. M. Barnes, J. C. LaManna, M. A. Smith
and K. L. Drew, manuscript submitted for publication). By contrast, other
heterothermic species, such as golden-mantled ground squirrels
(Spermophilus lateralis) and hedgehogs (E. europaeus), may
become hypoxic during torpor owing to long periods of apnea. These species
often breathe intermittently during hibernation, waiting up to 30 min or
longer between breaths. In hedgehogs, arterial oxygen partial pressure
(PaO2), sampled from chronic aorta cannula, is
higher in torpor than in the active state (120 vs 105 mmHg; 160
vs 14.0 kPa) but falls to 10 mmHg (1.3 kPa) at the end of the apneic
period lasting 5070 min (Tahti and
Soivio, 1975
). It is unclear if tissue becomes hypoxic during
periods of apnea since neither tissue lactate nor tissue oxygen tension has
been reported. Hemoglobin O2 affinity is typically higher in
hibernating species and even higher at cold temperatures. Thus, tissue hypoxia
may not be as high as indicated by the low
PaO2. In hibernating golden-mantled ground
squirrel, the P50 at 7°C and a pH of 7.46 was found to
be 5.8 mmHg (0.77 kPa; Maginniss and
Milsom, 1994
).
Neuroprotection against hypoxia during hibernation is thought to result
from synergy between multiple adaptations, including extreme hypothermia
(beyond what is tolerated by homeotherms), increased antioxidant defense,
metabolic suppression, immune modulation and decreased ion channel activity
(Fig. 1;
Drew et al., 2001).
Interestingly, one paradigm of ischemic preconditioning, found to attenuate
volume of infarction by
60%, induced changes in gene expression
reminiscent of adaptations observed in hibernating animals
(Stenzel-Poore et al., 2003
).
Using microarray analysis, preconditioning was found to induce changes in gene
expression consistent with suppression of metabolic pathways and immune
responses and reduction of ion channel activity
(Stenzel-Poore et al., 2003
),
all of which are characteristic of hibernation and thought to contribute to
neuroprotection in the hibernating state
(Drew et al., 2001
).
Stenzel-Poore et al. (2003
)
suggest that both hibernation and the protein-synthesis-dependent
preconditioning observed in their study are associated with an evolutionarily
conserved reprogramming of the cytotoxic cellular response. Of the numerous
adaptations exhibited by hibernating animals, metabolic suppression may be the
most novel and least well mimicked by current pharmacotherapies.
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Mechanisms of metabolic suppression |
---|
Mechanisms of metabolic suppression in hibernation are poorly understood.
During entrance into or arousal from hibernation, changes in oxygen
consumption, heart rate, respiratory rate and cerebral blood flow all precede
changes in core body temperature (Lyman,
1982; Toien et al.,
2001
; Osborne and Hashimoto,
2003
). These results argue for active regulation of metabolism
beyond that of temperature effects and support the model that parasympathetic
tone coordinates entrance into and maintenance of torpor while an increase in
sympathetic tone initiates arousal (Twente
and Twente, 1978
; Harris and
Milsom, 1995
; Milsom et al.,
1999
). Further evidence for regulated metabolic suppression that
goes beyond temperature effects comes from observations in the Arctic ground
squirrels, where body temperature and metabolic rate dissociate during
steady-state torpor over a range of ambient temperatures
(Buck and Barnes, 2000
). While
metabolic suppression during steady-state torpor cannot be explained entirely
by temperature effects in Arctic ground squirrels, or in other small
heterotherms (Geiser, 1988
),
this may not be the case in all heterothermic species. Zimmer and Milsom
(2001
) reported that in
golden-mantled ground squirrels oxygen consumption parallels core body
temperature, suggesting that, in this species, steady-state metabolism is not
lower than what is achieved through temperature-dependent suppression of
biochemical processes (Q10 effects).
A mechanism that may be central to metabolic suppression during entrance
into and maintenance of torpor involves a change in thermoregulatory set point
(Florant and Heller, 1977).
The mammalian thermostat is located in the preoptic anterior hypothalamus
(POAH), and cooling this area below the thermoregulatory set point evokes
thermogenesis, indicated by an increase in oxygen consumption. The
thermoregulatory set point (i.e. the temperature of the POAH that evokes
thermogenesis) decreases as animals enter hibernation, and this decrease
precedes the decrease in body temperature. Turning down the thermostat
abruptly decreases oxygen consumption and invokes coordinated cooling of core
body temperature via shunting of core blood to the periphery to
facilitate heat loss (Heller et al.,
1977
; Florant and Heller,
1977
). The subsequent drop in body temperature then facilitates
metabolic suppression through thermodynamic effects on metabolic processes
(Geiser, 1988
). This `black
box' thermostat thus appears to play a major role in metabolic suppression in
hibernation and metabolic response to hypoxia in the euthermic state
(discussed below). Unveiling mechanisms of the thermostat, as well as the
means that hibernating species use to tolerate such low body temperatures, may
lead to therapeutic strategies when oxygen delivery is limited. Stimulation of
the cerebellar fastigial nucleus protects against cerebral ischemia in rats
(Reis et al., 1997
), and this
effect may involve suppression of cerebral glucose metabolism. Involvement of
this pathway in hibernation has not been studied.
Other potential mechanisms contributing to metabolic suppression in
hibernation at the cellular level are ion channel arrest, increase in
inhibitory neurotransmission and suppression of substrate oxidation. Evidence
of ion channel arrest in hibernation comes from studies of Ca2+
uptake in brain and cardiac tissues
(Gentile et al., 1996;
Wang et al., 2002
).
Surprisingly, extracellular levels of the inhibitory neurotransmitter GABA
decrease in striatum during hibernation
(Osborne et al., 1999
), and
extracellular glutamate remains unchanged during steady-state torpor compared
with euthermic animals (Zhou et al.,
2001a
). Finally, studies in Arctic ground squirrel show evidence
of tissue-specific depression of substrate oxidation during hibernation. At an
assay temperature of 37°C, state 3 and state 4 respiration decrease in
liver mitochondria but not skeletal muscle mitochondria isolated from
hibernating ground squirrels (Barger et
al., 2003
). A decrease in substrate oxidation would decrease
oxygen consumption but could be due to a decrease in demand for ATP as well as
direct inhibition of the biochemical reactions necessary for substrate
oxidation. Barger et al. (2003
)
found no evidence for a decrease in futile proton leak in hibernating
mitochondria.
Importantly, hypoxia, anoxia or other forms of physiological stress are not
sufficient to induce hibernation in ground squirrels
(Bullard et al., 1960; K. L.
Drew, K. Cozad, Y. Ma, P. M. Rivera and H. Zhao, unpublished). This contrasts
with hamsters, where, after short-daylight-induced gonadal regression, food
and/or water deprivation is sufficient to induce torpor
(Lyman and Chatfield, 1955
).
While it is unclear what signaling events induce hibernation in ground
squirrels and other obligatory hibernators, they are linked to circannual
rhythm and the reproductive cycle. Gonadal regression and genesis precede
hibernation in the autumn and emergence from hibernation in the spring.
Non-circadian functions of the suprachiasmatic nucleus may coordinate
circannual rhythm (Dark et al.,
1990
), as well as the timing of interbout arousal episodes that
interrupt prolonged torpor throughout the hibernation season
(Ruby et al., 2002
). While
decreased oxygen demand may not explain all of the 28-fold increase in
survival time under 100% N2 in hibernating hedgehogs
(Biörck et al., 1956
),
10-fold decreases in oxygen consumption certainly have the potential to
enhance survival under conditions of limited oxygen and nutrient delivery to
vital organs, suggesting that mechanisms of metabolic suppression with
potential application in humans warrant further study.
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Hypoxia tolerance during euthermy: evidence and mechanisms |
---|
Do physiological adaptations necessary for successful hibernation, such as
the ability to restrict blood flow to vital organs during rewarming and to
vasodilate to facilitate body cooling during entrance into hibernation,
contribute to hypoxia tolerance? Hypoxia is known to decrease metabolism in
many vertebrates through cooling of core body temperature
(Barros et al., 2001). Cooling
is achieved via preference for cooler environments, body posture and
a decrease in POAH thermoregulatory set point and subsequent peripheral
vasodilation similar to what occurs during entrance into hibernation
(Tattersall and Milsom, 2003
).
Evidence suggests that the hypoxic metabolic response is of greater magnitude
in heterothermic species, presumably because the regulatory mechanisms are
similar to those used during entrance into hibernation
(Bullard et al., 1960
;
Burlington et al., 1969
;
Barros et al., 2001
).
Hypothermia, induced under controlled conditions, improves neurological
outcome after hypoxia and ischemia in animal models as well as in humans
following cardiac arrest (Busto et al.,
1987
; Globus et al.,
1995
; Hypothermia after
Cardiac Arrest Study Group, 2002
), although the multifactorial
mechanisms of protection are still poorly understood
(Holzer and Sterz, 2003
).
Magnitude of cooling may enhance protection until limit of cold tolerance is
reached (Huh et al., 2000
).
Thus, enhanced tolerance to decreased core body temperature due to adaptations
at the cellular level may play as great a role in tolerance to hypoxia as the
hypoxic metabolic response, because the latter requires low core body
temperature to be effective. Finally, coordinated cooling cannot fully explain
hypoxia tolerance in euthermic heterotherms. Bullard et al.
(1960
) found that at all
ambient temperatures, including those at which no body cooling was possible,
euthermic heterotherms outlived non-hibernating species and concluded that
temperature was not the only factor involved in hypoxia tolerance.
Other factors that could contribute to hypoxia tolerance in euthermic
heterotherms include higher levels of ketone bodies
(D'Alecy et al., 1990),
circannual suppression of immune response
(Sidky et al., 1972
),
antioxidant defense (Buzadzic et al.,
1997
), seasonal changes in metabolism
(Boyer et al., 1997
) and
differences in intrinsic tissue properties. Frerichs and Hallenbeck
(1998
) provide the only
evidence for differences in intrinsic tissue properties: at 36°C,
protection from oxygen glucose deprivation in hippocampal slices from
euthermic, 13-lined ground squirrels was better than rat (albeit not as good
as in slices from hibernating ground squirrels). Importantly, differences
between groups (hibernating ground squirrel, euthermic ground squirrel and
rat) were enhanced at colder temperatures. Further studies are warranted to
confirm intrinsic tissue differences and to address mechanisms of hypoxia
tolerance at the tissue level.
One cellular mechanism could involve a preconditioning-like phenomenon.
Curiously, cellular stress evidenced by elevated brain tissue levels of iNOS
(inducible nitric oxide synthase) and HIF-1 (hypoxia indicible factor
1
) and activation of ERK (extracellular-signal-regulated kinase) and
JNK/SAPK (c-Jun N-terminal kinase/stress-activated protein kinase) (Zhu et
al., 2004) are consistent with a state of preconditioning in euthermic Arctic
ground squirrels. Resting PaO2 values reported
for euthermic mammalian heterotherms are frequently below 80 mmHg (11 kPa;
Burlington et al., 1969
;
Frerichs et al., 1995
), and
evidence of mild, uncompensated, chronic hypoxia, indicated by low
PaO2, high
PaCO2, decreased pH and elevated levels of
HIF-1
, is consistently observed in euthermic Arctic ground squirrels
(Y. L. Ma, X. Zhu, P. M. Rivera, O. Toien, B. M. Barnes, J. C. LaManna, M. A.
Smith and K. L. Drew, manuscript submitted for publication). Although low
PaO2 may not translate directly to tissue
hypoxia because of increased hemoglobin oxygen affinity observed in other
species of heterotherms (discussed above; Maginnis and Milsom, 1994), elevated
PaCO2, decreased pH and associated upregulation
or activation of stress signaling pathways suggest that euthermic Arctic
ground squirrels experience mild, chronic stress. The functional significance
and cause-and-effect relationship between low
PaO2 and cellular stress in euthermic ground
squirrels remain to be determined; however, it is tempting to speculate that
mild, chronic hypoxia and associated cellular stress precondition these
animals to tolerate more severe hypoxia.
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Hypoxia tolerance as an adaptation to heterothermy per se |
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Hypoxia tolerance during arousal from hibernation: evidence and mechanisms |
---|
While potential mechanisms of hypoxia tolerance during torpor are numerous
and obvious, many of the neuroprotective aspects of hibernation begin to
subside during arousal thermogenesis. For example, while metabolic suppression
is pronounced during torpor, oxygen consumption peaks as animals work to
re-warm, precisely at the time of minimum PaO2
(Ma et al., 2004).
Nonetheless, studies in hamsters (Mesocricetus auratus) indicate that
energy charge in brain is maintained during arousal
(Lust et al., 1989
).
Production of ROS exceeding antioxidant capacity during hypoxia and
re-oxygenation damages cellular components directly via oxidative
modification as well as indirectly via activation of inflammatory and
pro-death signaling pathways. A generalized adaptation of hypoxia-tolerant
animals may be increased antioxidant defense mechanisms to protect cells from
ROS during re-oxygenation (Hermes-Lima and
Zenteno-Savin, 2002
). Ascorbate, one of the most important
low-molecular-mass antioxidants in plasma, increases 4-fold in plasma and
doubles in cerebral spinal fluid (CSF) during hibernation
(Drew et al., 1999
;
Toien et al., 2001
). While ROS
generation is expected to be low during hibernation, in part due to suppressed
flux of oxygen through the electron transport chain, generation of ROS is
assumed to increase during arousal thermogenesis in parallel with pronounced
increases in oxidative metabolism. In spite of the surge in metabolism,
concomitant with a decline in PaO2 during
arousal thermogenesis, no evidence of oxidative modification in brain has been
observed following arousal from hibernation
(Ma et al., 2004
). Evidence
suggests that redistribution of ascorbate from plasma to metabolically active
tissues during arousal protects tissues from oxidative modification
(Toien et al., 2001
). Indeed,
plasma ascorbate concentrations decline in parallel with peak oxygen
consumption (Toien et al.,
2001
), and brain ascorbate concentrations increase significantly
towards the end of arousal (Ma et al.,
2004
).
Hypoxia-reoxygenation promotes neuronal injury, in part via toxic
inflammatory mediators produced by activated microglial cells and infiltrating
leukocytes. SAPKs, a family of serine/threonine kinases including JNKs and
p38, are part of a phosphorelay system that regulates cellular activities
(Johnson and Lapadat, 2002).
Activation of JNK and p38 by environmental stressors such as hypoxia often
leads to cell death via inflammation and apoptosis and comprises part
of the signal transduction cascade involved in neurodegenerative hypoxia
(Kunz et al., 2001
;
Fig. 2).
|
Analysis of SAPK activation in the brain following arousal from hibernation
is consistent with activation of an attenuated stress response. Recent results
show that, while JNK is activated during arousal, p38 is not activated
following arousal in bats or Arctic ground squirrels
(Lee et al., 2002; Zhu et al.,
2004). Furthermore, iNOS, known to be induced downstream of p38 activation
(Park et al., 2002
), is not
induced by arousal in Arctic ground squirrels (Zhu et al., 2004).
Interestingly, circulating leukocytes rapidly return to euthermic values, and
the acute-phase response to bacterial lipopolysaccharide (LPS) is fully
restored (Toien et al., 2001
;
Prendergast et al., 2002
).
Nonetheless, failure to activate p38 or induce iNOS argues for sufficient
modulation of the immune response during arousal to prevent a fully developed
inflammatory stress response.
Finally, oxygen delivery to tissues may be enhanced during arousal, as
hemoglobin with high oxygen affinity in the hibernating state transitions to
hemoglobin with lower oxygen affinity in the euthermic state
(Maginniss and Milsom, 1994).
The combined effects of hypothermia, enhanced antioxidant defense mechanisms,
attenuation of the inflammatory response, as well as enhanced oxygen delivery,
thus have the potential to provide significant protection against hypoxia
during arousal.
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Regeneration or protection from degeneration? Evidence for synaptogenesis following arousal thermogenesis |
---|
JNK/SAPK is a potential signaling crossroads between degeneration and
regeneration that may be tipped towards a regenerative outcome under
physiological conditions of arousal thermogenesis. JNK/SAPK is one of the
major molecules activated by deleterious stimuli such as UV irradiation,
hypoxia, free radicals and cytokines. Although, in many cases, the activation
of JNK/SAPK leads to cell death, such as is seen in hypoxia-induced apoptosis
in hepatocytes and developing brain neurons
(Crenesse et al., 2000;
Chihab et al., 1998
;
Kunz et al., 2001
), the
activation of JNK/SAPK has also been shown to mediate hypoxia-induced
expression of basic fibroblast growth factor (bFGF) and hypoxia-induced
proliferative responses of fibroblasts
(Das et al., 2001
;
Le and Corry, 1999
). More
recently, JNK activity has been shown to be essential for late-stage
neuritogenesis in N1 cell cultures and suggested to be involved in late stages
of functional differentiation such as synaptic connection formation
(Xiao and Liu, 2003
). JNK
activation, in the absence of neuronal pathology during arousal
(Ma et al., 2004
; X. Zhu, M.
A. Smith, G. Perry, Y. Wang, P. M. Rivera, A. P. Ross, H. W. Zhao, J. C.
LaManna and K. L. Drew, manuscript submitted for publication), and
synaptogenesis shortly after arousal
(Popov et al., 1992
) argue
that activation of JNK/SAPK during arousal may reflect an effort to mobilize
regenerative rather than apoptotic processes.
In summary, heterothermic mammals possess a repertoire of neuroprotective
adaptations that are hypothesized to contribute to hypoxia tolerance.
Tolerance is most pronounced in the hibernating state, although hibernating
animals are not hypoxic due to 10-fold decreases in oxygen demand. Like
hibernating animals, euthermic heterotherms tolerate hypoxia better than
homeotherms. This tolerance is hypothesized to stem from adaptations necessary
for successful hibernation. Curiously, euthermic Arctic ground squirrels
appear to be mildly, but chronically, hypoxic at normal atmospheric pressures
and oxygen tensions. The ability to tolerate hypoxia may be necessary for
successful arousal thermogenesis, where PaO2
decreases in parallel with increased oxygen consumption. It is hypothesized
that, during arousal, selective activation of JNK/SAPK via
attenuation of hypoxia-induced stress tips the outcome of activation of SAPK
towards regeneration.
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Acknowledgments |
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Footnotes |
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