Published online before print October 27, 2005, doi: 10.1161/01.STR.0000189996.71237.f7
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(Stroke. 2005;36:2781.)
© 2005 American Heart Association, Inc.
Progress Reviews |
The Role of Protein Kinase C in Cerebral Ischemic and Reperfusion Injury
From the Stanford University School of Medicine, California.
Correspondence to Daria Mochly-Rosen, Stanford University School of Medicine, CCSR, Room 3145A269 Campus Dr, Stanford, CA 94305-5174. E-mail mochly{at}stanford.edu
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Abstract |
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Top
Abstract
IntroductionBackground and Purpose— Stroke is a leading cause of disability and death in the United States, yet limited therapeutic options exist. The need for novel neuroprotective agents has spurred efforts to understand the intracellular signaling pathways that mediate cellular response to stroke. Protein kinase C (PKC) plays a central role in mediating ischemic and reperfusion damage in multiple tissues, including the brain. However, because of conflicting reports, it remains unclear whether PKC is involved in cell survival signaling, or mediates detrimental processes.
Summary of Review— This review will examine the role of PKC activity in stroke. In particular, we will focus on more recent insights into the PKC isozyme-specific responses in neuronal preconditioning and in ischemia and reperfusion-induced stress.
Conclusion— Examination of PKC isozyme activities during stroke demonstrates the clinical promise of PKC isozyme-specific modulators for the treatment of cerebral ischemia.
Key Words: cerebral infarction • cerebral ischemia • neuroprotection
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Introduction |
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Stroke is the third leading cause of death in the United States, with >700 000 new incidents occurring each year.1 Yet, we can claim only a modest understanding of the complex network of cellular processes that regulates cerebral injury. Although multiple agents have demonstrated efficacy in reducing stroke injury in preclinical studies, the only currently approved drug for stroke patients is a thrombolytic, tissue plasminogen activator. However, the narrow therapeutic window (3 hours after stroke onset) and associated risks, including hemorrhage,2 translate to limited therapeutic use; <2% of stroke patients in the United States receive tissue plasminogen activator.3 The great need for a new generation of agents that confer neuroprotection against ischemic/reperfusion injury and extend the therapeutic window is clear.
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Molecular Mechanisms of Cerebral Ischemic and Reperfusion Injury |
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Multiple cellular processes are rapidly activated in response to ischemic/reperfusion-induced stress. The ischemic core, a region of tissue that is immediately distal to an occluded artery, undergoes rapid, anoxic cell death within minutes of ischemia onset. Irreversible processes including mitochondrial collapse, rapid energy depletion, and ion pump failure result in large increases in intracellular calcium, extracellular potassium, and edematous cell swelling, characteristic of necrotic cell death.4,5 However, in the ischemic penumbra, or "shadow" surrounding the core, metabolism and intracellular signaling cascades are maintained partly by hypoperfusion from a diminished collateral blood supply.6 The penumbra is considered "at-risk" tissue, affected by multiple stresses including regional glutamate and potassium diffusion and peri-infarct depolarizations emanating from the ischemic core.7,8 Importantly, the effects of reperfusion, the return of blood flow into an ischemic area after arterial recanalization, may contribute significantly to stroke damage.4,9
It is now recognized that ischemia and reperfusion initiate different intracellular responses.5 During reperfusion, the inability of impaired mitochondria to use oxygen in electron transport results in reduction in cellular ATP levels, production of reactive oxygen species (ROS), expression and activation of proapoptotic signaling intermediates, and initiation of inflammatory processes.4,10 Reversing or halting some of these processes can reduce damage,11–13 suggesting that delivering neuroprotectants, even at reperfusion, may lead to improved neurological outcome.
Salvage of "at-risk" tissue depends on reversing or arresting detrimental intracellular processes that control propagation of the infarct beyond the necrotic core. In tissue with residual energy levels, such as the ischemic penumbra, rapid changes occur in the activity of many different signaling paths, involving diverse protein kinase families. Alterations in the expression or activity of calcium/calmodulin-dependent protein kinase II, mitogen-activated protein kinase (MAPK) family members c-Jun N-terminal kinase and extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and protein kinase C (PKC) suggest that multiple kinases participate in the response of the tissue to ischemia and reperfusion.14–18 The role of PKCs in mediating stroke injury has received particular attention. PKC activity has been seen in ischemic injury in multiple tissues, including heart,19 liver,20 and kidney,21 suggesting it is involved in a conserved ischemic response pathway. However, whether PKC mediates or is simply activated during ischemic injury is controversial because of mixed reports on PKC expression and activity, and thus is the focus of this review.
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The PKC Family |
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The PKC family of serine/threonine kinases consists of 10 different isozymes. In the brain and spinal cord, PKC
, PKCß1, PKCß2, PKC
, PKC
, PKC
, PKC
, PKC
, and PKA
mRNA and protein are present and demonstrate unique tissue, cellular, and subcellular localizations.22,23 However, the relative levels of PKC isozyme expression in different anatomic brain regions have not yet been examined in detail, and alterations in the expression and levels of these isozymes under conditions of cerebral ischemic stress have not been systematically examined. Importantly, individual PKC isozymes mediate different and sometimes opposing functions after activation by the same stimulus.24 However, the use of nonspecific pharmacological tools conceals the role of individual PKC isozymes, contributing to inconsistency in reports on PKC function. With the availability of isozyme-specific modulators, the unique roles of each PKC isozyme are becoming increasingly clear (note 1; Table 1).
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PKC Activity in Stroke Models |
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When exposed to sublethal ischemic episode, the brain enacts endogenous neuroprotective mechanisms to induce tolerance, rendering it protected against a subsequent lethal transient ischemic attack. Two temporal waves of preconditioning have been described: a rapid induction phase, mediated in part through adenosine, ATP-sensitive potassium (K+ATP) channels, and low-level glutamate-induced calcium flux,25,26 and a delayed induction window, likely to rely on altered gene expression and protein synthesis.5,27 Multiple agents induce rapid tolerance in the brain, including exposure to low levels of N-methyl-D-aspartate (NMDA),28 NO,29 and adenosine.30 Ischemic tolerance induced by these endogenous preconditioning agents is dependent on PKC activation,26,28,31 suggesting that PKCs are key regulators of ischemic preconditioning in the brain.
A largely conflicting body of reports has emerged concerning the PKC response to ischemia (Table 2). Some studies demonstrate that total PKC levels and activity are increased at very early time points after ischemia in vivo32–34 and after oxygen and glucose deprivation (OGD) and excitotoxic damage in vitro.35 Inhibition of PKC using high concentrations of phorbol 12-myristate 13-acetate, or nonspecific PKC inhibitors such as H7, calphostin C, or staurosporine, protect cells against NO-, anoxic- or glutamate-induced excitotoxic cell death in vitro36,37 and against ischemic damage in vivo.38 These data suggest that PKC is activated and plays a damaging role during stroke. However, a greater majority of studies report a rapid loss of total PKC activity and expression after ischemia, suggesting PKC is degraded.39–42 This loss of total PKC activity, also seen in in vitro culture models of ischemic and excitotoxic cell death,43,44 correlates with neurodegenerative processes,45 implying that maintaining PKC activity may confer protection against excitotoxic damage. These apparently conflicting reports may stem from examination of varying animal models, brain regions, duration and intensities of ischemic/reperfusion insult, and may be compounded by the different, possibly opposing roles of individual PKC isozymes.
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The mechanisms by which PKC is activated during stroke are likely to be multifactorial. Here, we focus on 3 specific PKC isozymes and examine their roles in widely studied processes: (1) adenosine-mediated upregulation of PKCs in the context of ischemic tolerance (preconditioning), and, in particular, the role of PKC; (2) PKC response to glutamate-induced excitotoxicity during ischemia, focusing on the neuronal PKC isoform; and (3) PKC activation in delayed apoptotic processes during reperfusion. However, changes in PKC activity and expression in response to other ischemic/reperfusion processes have been reported, including inflammatory processes (as discussed with reference to PKC below), cell necrosis, and alterations in microvascular tone and reactivity.46,47
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Ischemic Tolerance: Role for PKC
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The role of
PKC in ischemic injury has been subject to debate.26,48 Some reports demonstrate sustained activation of PKC after OGD35,49 and, in response to kainic acid, a glutamate analog.50 Other reports suggest that PKC is not activated in response to ischemia51,52 in an in vivo model of spreading depression by cortical KCl application or by ischemic preconditioning.31,53 PKC mRNA increases slightly at 1 hour after reperfusion; however, more significant upregulations were observed in the transcription of other PKC isozymes.54 Importantly, many of these reports focus on the RNA, protein, and activity levels of PKC during the reperfusion period. However, a potential role for PKC may exist during ischemia or after less severe injuries.
Studies using PKC isozyme-selective modulators have demonstrated that PKC is required for induction of ischemic tolerance; delivery of an PKC inhibitor peptide abates NMDA-induced preconditioning in cell culture and isolated hippocampal slice models.28 Correspondingly, delivery of an PKC-specific activator peptide reduces damage, as measured using lactate dehydrogenase (LDH) release, when delivered before OGD in pure neuronal and mixed neuronal/astrocyte cultures.49 Importantly, the protective effect of the PKC activator was lost when delivered after OGD in these models. These data suggest that changes occur in PKC activity over the time course of ischemic injury and begin to address the cell type-specific effects of PKC.
The molecular basis of PKC-induced protection is unclear. One mechanism (Figure 1) implicates adenosine and the mitochondrial K+ATP (mK+ATP). Under metabolic stress such as ischemia, increases in adenosine levels (in addition to bradykinin and opioids) initiate a series of intracellular signaling events via G-protein-coupled receptor signaling, leading to activation of phospholipases, production of di-acylglycerol (DAG), calcium influx, and PKC activation.55 Multiple studies have now demonstrated that adenosine administration protects neuronal cells against ischemic-type injury via PKC,30,56,57 and more recent work has identified a role for PKC in particular.57 Treatment of primary neuronal cultures with N6-(R)-phenylisopropyladenosine, an A1 adenosine receptor agonist, causes extended activation of PKC (6 hours after treatment), whereas delivery of an PKC-selective inhibitor peptide blocks adenosine-induced neuroprotection against this chemical ischemia.57 Adenosine-mediated PKC signaling is mediated in part through ERK, a MAPK family member that has been implicated in antiapoptotic signaling.58 Interestingly, studies in cardiac mitochondria demonstrate that PKC forms functional modules with MAPK family members to maintain mitochondrial function, including inhibiting deleterious Bcl-2 associated death domain protein (BAD; a Bcl-2 family member) activity.59 PKC activity at the mitochondria may also contribute to regulation of mK+ATP channels, important for preserving mitochondrial membrane potential, maintaining energy and reducing calcium influx during metabolic challenge.60–62 PKC is thought to mediate the activity of this channel through direct phosphorylation63 and regulation of its internalization.64 In particular, reports in cardiac ischemia models suggest PKC mediates adenosine-induced preconditioning via K+ATP function.65–67 These data suggest that PKC confers cerebral ischemic protection, in part by maintaining mitochondrial function via ERK activity and potentially by mediating adenosine-induced mK+ATP channel function.
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Ischemia and the Role of Neuronal PKC
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One of the central events that contributes to injury during and after ischemic stroke is the release of the excitatory amino acid glutamate. Extrasynaptic glutamate causes waves of peri-infarct depolarization in surrounding cells and spreading neuronal death. In part, via NMDA receptors (NMDARs), glutamate induces an influx of calcium and sodium into the cell, leading to release of intracellular calcium stores, lipid peroxidation, and generation of free radicals.4 These events lead to rapid activation and increased expression of multiple PKC isozymes, as seen after glutamate, KCl or kainic acid application in vitro and in vivo.50,68–72 Correspondingly, PKC inhibition reduces NMDA-mediated neurotoxicity,37,73,74 suggesting that PKC isozymes may mediate excitatory amino acid-induced signaling.
PKC is expressed exclusively in neurons of the brain and spinal cord.75 Therefore, this isozyme may play a central nervous system (CNS)–specific role in mediating response to ischemic injury. PKC is activated rapidly during ischemia in various models,17,52,76–78 consistent with increases in intracellular calcium and phospholipid metabolism during ischemia, required for PKC activation. The use of PKC knockout mice suggest PKC may play a detrimental role during cerebral ischemic injury; PKC knockout mice have significantly smaller infarcts, as measured using histological techniques, compared with wild-type animals after permanent ischemia.79 However, in an in vitro model of OGD, inhibition of PKC using a PKC-selective peptide inhibitor had no effect on cell survival, as assayed by LDH release.49
Multiple reports now suggest that PKC may be involved in a positive feedback loop to potentiate NMDAR activity,44,80 worsening calcium loading, mitochondrial dysfunction, and promoting cell death (Figure 2).81 Modulating NMDAR activity may be attributable to direct phosphorylation of NR1 receptor subunits by PKC,82 although recent evidence suggests PKC indirectly mediates NMDAR via regulation of associated scaffolding proteins83 or Src-family tyrosine kinase activity.84 In particular, PKC may regulate this feedback; PKC interacts with NMDAR subunits in vivo to regulate postsynaptic excitotoxic signaling.85 However, indirect evidence also indicates that ß1PKC and ß2PKC subspecies may also modulate NMDAR function.73,86
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After extended ischemic injury and reperfusion, changes in PKC activity are less clear. Several reports demonstrate that PKC becomes inactive and downregulated,44,87 as occurs after prolonged PKC activity,88 whereas others report that PKC is activated specifically during reperfusion.17,78 In fact, a contrasting role for PKC has been suggested during reperfusion; PKC knockout mice demonstrate worsened injury after a transient ischemia, suggesting PKC may mediate beneficial signaling processes during reperfusion injury.13
Together, these data suggest that PKC may play a deleterious role during early ischemic injury or permanent ischemic injury, potentially activated by DAG formation and flux of intracellular calcium that occur during early ischemic signaling. During ischemia, PKC may be involved in potentiating NMDAR function, leading to calcium overloading and cell death. However, after reperfusion, PKC may play an opposite role: mediating protective signaling and reducing cell death. These data demonstrate that individual PKC isozymes may play differing or opposing roles at different stages of injury, underscoring the importance of studying PKC isozyme function during different periods of cell death by examining transient and permanent ischemia models.
Other PKC isozymes are also likely to be involved in mediating the cellular response to ischemia in the brain. For example, PKC mediates NMDA-induced injury in primary neuronal cultures; inhibition of PKC reduces cellular damage, as monitored by LDH release.74 A more detailed understanding of the molecular mechanism by which PKC elicits death in response to NMDA toxicity awaits further study.
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PKC in Reperfusion Injury: Apoptosis, Necrosis, and Inflammation
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With increasing evidence that cerebral reperfusion generates its own host of detrimental intracellular signaling cascades and contributes to expansion of the ischemic infarct, the concept that reperfusion injury is a potent mediator of cell death is now widely accepted. Understanding reperfusion-induced processes is of particular interest for therapeutic targeting in combination with established thrombolytic therapy or mechanical recanalization techniques.
Multiple lines of data suggest that PKC plays an important role in mediating cerebral reperfusion injury. In particular, PKC has been implicated in mediating oxidative stress, apoptosis, and inflammation, hallmarks of reperfusion injury.89,90 Studies demonstrate that PKC is specifically upregulated and rapidly activated in response to reperfusion-induced intracellular signaling; in transient focal and global ischemia models, PKC mRNA is upregulated within 24 hours after ischemia, as seen in perifocal cortex and in CA1 neurons, respectively.51,91,92 Concomittantly, PKC protein levels are increased in the perifocal region during reperfusion,92 suggesting a role for this enzyme in mediating delayed-injury processes. Studies in an in vivo transient ischemia model show PKC is rapidly activated at the onset of reperfusion, although this activity is not sustained at 24 hours after ischemia.93
How PKC mediates reperfusion injury, whether increasing activity of this enzyme promotes or reduces reperfusion injury, has only more recently been addressed. Studies using 2 very different approaches, pharmacological agents and knockout animals, indicate that PKC plays a detrimental role after stroke in vivo. Delivery of the PKC-specific inhibitor peptide V1-1 significantly reduced ischemic injury when delivered over an extended time window of reperfusion after a 2-hour middle cerebral artery occlusion in vivo, as assessed by histological staining techniques, and in an in vitro hippocampal slice model subject to OGD, as assessed by propidium iodide staining of CA1 neurons. However, this protective effect was not seen when V1-1 was delivered before ischemia, suggesting that PKC specifically mediates reperfusion-induced cell death in parenchymal cells of the brain.93 A complementary study using PKC knockout mice demonstrates that PKC may contribute to damage by mediating inflammatory processes during reperfusion damage; PKC knockout mice have smaller infarcts after transient focal ischemia compared with wild-type animals and demonstrate reduced neutrophil invasion into infarcted tissue. Further, wild-type animals that received bone marrow transplants from PKC knockout donor mice also demonstrate reduced ischemic injury,47 suggesting that PKC activity in neutrophils, rather than neuronal or glial cells, is critical in this response.
A rapidly growing body of reports suggests a specific role for PKC in mediating apoptotic processes in a variety of cell types.89,94 Apoptosis occurs largely in a delayed fashion during cerebral reperfusion, correlating with the reported increases in PKC activation and expression, as described above. Reduced energy levels, as seen in the ischemic penumbra as well as spreading waves of depolarization, induce the generation of ROS such as hydroxyl radicals, superoxide, and singlet oxygen.95 PKC is responsive to ROS52,90,96 and other apoptotic mediators including caspase activation.97 In the heart, PKC translocates to the mitochondria in response to oxidative stress,90 where it mediates superoxide production, pyruvate dehydrogenase inhibition, reduced ATP generation, and increased free radical formation.98,99 Inhibition of PKC translocation reduces mitochondrial dysfunction, including Bcl-2 family protein dimerization and release of apoptogenic factors, and increases the rate of ATP regeneration and correction of cellular acidosis.94,100 Parallel findings have been demonstrated in a cerebral ischemia models. After transient focal ischemia, delivery of a PKC inhibitor peptide reduced apoptotic cell death, as seen by TUNEL staining, increased antiapoptotic Akt (protein kinase B) activity, and reduced BAD translocation out of the cell cytosolic fraction, indicating reduction of BAD deleterious activity.93 In a rat cardiac arrest model, PKC is activated via caspase-3–mediated cleavage in hippocampal CA1 neurons, contributing to reperfusion-induced hippocampal injury (Figure 3). 101 The role of PKC in promoting reperfusion-induced apoptotic cell death suggests it is an important therapeutic target for extended time windows after stroke injury in patients.
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PKC in Stroke: Unanswered Questions and Potential Clinical Implications |
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A promising body of work supports a role for
3 different PKC isozymes in mediating stroke-induced damage, with unique functions in preconditioning, in ischemia, and in reperfusion-induced signaling. Parallel findings concerning the positive or negative role of these isozymes in multiple models of ischemic/reperfusion damage, including focal and global ischemia models, suggest that PKCs may play an important role in mediating damage in multiple anatomical territories of the brain and brain injury paradigms. However, this underscores the need for more detailed studies about the distribution and activity of individual PKC isozymes in response to different stages and intensities of injury, different brain regions, different cell types, and different subcellular localizations. Identifying the roles for PKC in mediating endothelial cell dysfunction,102 maintenance of microvascular permeability,103 and cerebral vasospasm46 will provide a more comprehensive understanding of PKC function in cerebral ischemic/reperfusion injury. Finally, elaborating our understanding of the specific signaling pathways in which PKC participates, including different downstream effectors in different phases of stroke injury, will be critical to developing PKC-based therapeutic strategies.
The use of PKC-isozyme selective tools has demonstrated the importance of PKC signaling in mediating cerebral ischemic/reperfusion injury. However, further studies on the role of PKC isozymes in CNS ischemia are needed. Work to date has been performed largely in rodent models without translation to other animal models including primates and often does not include dose-response or long-term behavioral outcome analysis. The Stroke Therapy Academic Industry Roundtable criteria for evaluating preclinical drugs is therefore not complete.104 However, current research strongly suggests that regulating individual PKC isozymes has therapeutic value in 3 scenarios of CNS ischemic damage: (1) predictable CNS ischemia, (2) damage that occurs during transient ischemia followed by reperfusion, and (3) damage that occurs because of a permanent occlusion. Present data suggest that different PKC regulation should be used in the above 3 scenarios as follows. For predictable ischemia, such as that occurring during bypass surgery, it appears that PKC activation before ischemic event will provide optimal outcome. For transient, unpredictable ischemia, treatment with a short-acting PKC inhibitor early during ischemia, and with a long-acting PKC inhibitor or PKC selective activator during reperfusion, will provide optimal therapy. Finally, in cases of permanent occlusion, treatment with a PKC inhibitor and a PKC inhibitor should be protective. Clearly, more work in animal models is required before the current findings are translated to human studies. If substantiated, selective PKC regulators will open new avenues for the treatment of CNS ischemia and stroke.
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Note 1: Experimental Approaches to Study PKC Activity |
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The majority of commonly used pharmacological tools to study PKC function are nonspecific, altering the function of non-PKC kinases, or are nonselective for individual PKC isozymes. Designing agents that target individual PKC isozymes has been particularly difficult because of the high degree of homology between individual PKC isozymes and broad substrate specificity.105,106 Commonly used pharmacological agents include the H7 and staurosporine family members calphostin C, rottlerin, and chelerythrine (Table 1). Although exhibiting potent inhibition of PKC, these agents also inhibit other protein kinases (as catalytic domain inhibitors) and usually show no discriminatory activity on individual PKC isozymes. More comprehensive reviews of PKC-modulating compounds are given previously.105,106
The technical limitations of kinase selectivity and specificity have been addressed, in part, by the development of peptide activators and inhibitors of individual PKC isozymes that regulate subcellular localization of each isozyme.107,108 These peptides were developed based on a rational design strategy that capitalizes on the unique interaction between each PKC isozyme with an isozyme-specific anchoring protein, receptor for activated C kinase (RACK), necessary for PKC function; the RACKs anchor each activated isozyme near their substrates. Peptide inhibitors competitively block the translocation and interaction of PKC with its RACK, blocking access to substrates and therefore downstream physiological signaling. PKC-derived peptide agonists act as allosteric agonists by preventing intramolecular autoinhibitory interactions within PKC, leading to selective activation of individual PKCs by enabling their anchoring to the corresponding RACKs.109 The effect and isozyme selectivity of these peptides have been demonstrated in numerous systems, including in vitro and in vivo CNS models.49,74,93 The peptides can be effectively delivered to a number of tissues, including the brain after intra-arterial and intraperitoneal injections and subcutaneous pump delivery,93,110,111 to modulate the activation of individual PKC isozymes in vivo. A list of PKC peptide activators and inhibitors is given in Table 1.
A useful review on this subject was published while this paper was under review: Chou WH, Messing RO. Protein kinase C isozymes in stroke. Trends Cardiovasc Med. 2005;15:47–51.
Received March 7, 2005; revision received July 21, 2005; accepted August 18, 2005.
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