STAT transcription in the ischemic heart.

2012·0.55 MB·English

by  Knight, Richard A.

SPECIALFOCUSREVIEW:JAK-STATSIGNALINGINTHEMYOCARDIUM
JAK-STAT1:2,111–117;April/May/June2012;G2012LandesBioscience
STAT transcription in the ischemic heart
Richard A. Knight,1 Tiziano M. Scarabelli2 and Anastasis Stephanou1,*
1MedicalMolecularBiologyUnit;UniversityCollegeLondon;London,UK;2CenterforHeartandVesselPreclinicalStudies;St.JohnHospitalMedicalCenter;
WayneStateUniversityMedicalSchool;Detroit,MIUSA
Keywords: STAT1, STAT3, JAK, ischemia, myocardial infarction, hypertrophy, preconditioning, cardioprotection
Abbreviations:AT,angiotensin;CHD,coronaryheartdisease;CM,cardiacmyocytes;CT-1,cardiotrophin1;EGCG,epigallocatechin3
gallate;IL,interleukin;I/R,ischemiareperfusion;JAK,Januskinase;LIF,leukemiainhibitoryfactor;PIAS,proteininhibitorofactivated
STATs;PKC,proteinkinaseC;RISK,reperfusioninjurysalvagekinase;SOCS,suppressorofcytokinesignaling;STAT,signaltransducers
andactivatorsoftranscription;SAFE,survivoractivatingfactorenhancement;TNF,tumornecrosisfactor
have been genetically deleted in mice, although only STAT3
AllsevenSTATproteinsareexpressedintheheart,andinthis
deletion is embryonically lethal, suggesting that it plays a major
reviewwewillfocusontheircontributiontocardiacphysiology
and to ischemic heart disease and its consequences. A developmental role.
substantial literature has focused on the roles of STAT1 and Bindingofanumberofextracellularligands,suchascytokines,
STAT3 in ischemic heart disease, where, at least in the acute to their cognate receptors activates members of the Janus kinase
phase, they appear to have a yin-yang relationship. STAT1 (JAK) family, of which there are four members, JAK1, JAK2,
contributestothelossofirreplaceablecardiacmyocytesbothby JAK3 and TYK2 (only JAK1, JAK2 and TYK2 are expressed in
increasing apoptosis and by reducing cardioprotective the heart). In turn, JAKs recruit and activate specific STAT
autophagy.Incontrast,STAT3iscardioprotective,sinceSTAT3-
proteins, and JAK-activated STATs translocate to the nucleus
deficientmicehavelargerinfarctsfollowingischemicinjury,and
where they transactivate target genes.
anumberofcardioprotectiveagentshavebeenshowntoact,at
STATs are also inhibited by a number of mechanisms.
leastpartly, through STAT3 activation. STAT3 is alsoabsolutely
requiredforpreconditioning—aprocesswhereperiodsofbrief Cytokines which activate STATs also induce expression of
suppressors of cytokine signaling (SOCS), which form a classical
ischemia protect against a subsequent or previous prolonged
ischemic episode. Prolonged activation of STAT3, however, is negative feedback loop. The protein inhibitors of activated
strongly implicated in the post-infarction remodeling of the STATs (PIAS) also inhibit STAT activity, though these are not
heartwhichleadstoheartfailure,where,possiblytogetherwith specific inhibitors of STAT proteins. In addition, STATs can be
STAT5,itaugmentsactivationoftherenin-angiotensinsystem. targeted for proteasomal degradation by a number of ubiquitin
E3 ligases.
STATs in Cardiac Physiology
Introduction
The heart is dependent, to a greater degree than many other
The signal transducer and activator of transcription (STAT) organs, on alarge supply of high energy phosphates generatedby
family contains seven members, STAT1, STAT2, STAT3, mitochondrial respiration. It has been calculated that, in the
STAT4, STAT5A, STAT5B and STAT6 (reviewed in ref. 1), canine heart, basal ATP turnover is of the order of 5 mg/g/min2
allofwhichareexpressedintheheart.Allhaveasimilarmodular and this can increase by up to 10-fold under conditions of
structure, including an N-terminal oligomerization domain, a extreme exercise.2 The mechanisms by which change in ATP
coiled-coiled domain, a DNA binding domain, and linker, SH2 consumption is coupled to change in ATP production remain
and C-terminal transactivation domains. However, despite this onlypartiallyunderstood,althoughmitochondrialCaclearlyplays
structural similarity, there is considerable functional diversity a role,3 but STAT proteins, and in particular STAT3, may also
betweenthesesevenproteins.Therearetwokeyresiduesbetween contribute.
the SH2 domain and the C-terminus (for example, tyr701 and Small amounts (roughly 10% of the cytoplasmic levels) of
ser727 in STAT1), whose phosphorylation is required for STAT3 have been found in the mitochondria of several organs,
maximum transcriptional activity and for homo- and hetero- including the heart.4 STAT3 null cells show reduced oxygen
dimerization. All STATs can form homodimers or higher order consumption,whichappearstopredominantlyaffectComplexesI
structures, with the exception of STAT2, which can only and II, and STAT3 binds to Complex I (and possibly Complex
heterodimerize with STAT1. All the individual STAT proteins II), an interaction which requires Ser but not Tyr phosphoryla-
tion.4,5 However, it has been disputed whether this occurs
physiologically for stoichiometric reasons,6 although previous
*Correspondenceto:AnastasisStephanou;Email:[email protected]
studieshavedemonstratedaninteractionbetweenSTAT3andthe
Submitted:01/13/12;Revised:03/16/12;Accepted:03/20/12
http://dx.doi.org/10.4161/jkst.20078 Complex I component, GRIM-19, which does not apparently
www.landesbioscience.com JAK-STAT 111
require the STAT3 C-terminus.7,8 In addition, the deacetylase, radical scavenger, Tempol, a known cardioprotective agent,
SIRT-1, regulates STAT3 activity, and Sirt-1 null cells have inhibits tyrosine phosphorylation of STAT1, an effect that is
increased phospho-STAT3 with a parallel increase in mitochon- reversed by gamma interferon.20 Similarly, another antioxidant,
drialbioenergetics.9Clearly,moreworkisrequiredtoclarifysome epigallocatechin-3-gallate (EGCG), a component of green tea,
of these inconsistencies, and, in particular, to assess whether exerts cardioprotective effects in parallel with a reduction in
STAT3 null cardiac myocytes are as able to increase ATP STAT1 activation.21 The free radical link cannot be the whole
productionaswild-typecells.NootherSTAThasbeenimplicated story,however,sinceotherflavonoidsthatexertbothanti-oxidant
inpotentialinteractionandregulationofelectrontransportchain and STAT1 inhibitory actions are more potent cardioprotective
Complexes,althoughintumorsSTAT1transcriptionallyregulates agents than those that only have anti-oxidant activity.22 Indeed,
expression of a number of metabolic genes, including those EGCGhasbeenshowntoinduceexpressionofSOCS1,aknown
involved in glycolysis and the citric acid cycle as well as oxidative inhibitor of STAT1.23
phosphorylation.10 However, these long-term transcriptional The role of STAT1 in CM apoptosis can only be confined to
effectscannotcontributetotherapidchangesinATPproduction itsinitiation,sinceSTAT1isoneoftheseveralhundredsubstrates
in response to increased energy consumption. cleavedbycaspases,particularlycaspase-3,duringexecutionofthe
In contrast to STAT3, relatively little is known about the apoptotic program.24
contribution of other STATs to cardiac physiology. STAT1 has Incontrastwiththerelativelyextensiveliteratureontheroleof
been detectedin cardiac mitochondria,11and ROS production in STAT1 in apoptotic death, there is scant evidence implicating
responsetoTNF-ahasbeenreportedtobereducedinliversfrom STAT1 in other death subroutines. It has been reported that
STAT1knockoutmice,12althoughwhethermitochondrialcardiac autophagyenhancesgammainterferon-mediatedSTAT1tyrosine
STAT1 contributes to changes in cardiac bioenergetics is phosphorylation in macrophages,25 although a recent report
unknown. suggeststhat,perhapsparadoxically,heartsfromSTAT1deficient
mice are protected from I/R injury because of increased
STATs in Cardiac Pathology autophagy.26 This would suggest that STAT1 activation in the
heart challenged by I/R is harmful in two ways: it is directly
Ischemicheartdisease.Over180,000peopledieeachyearinthe implicated in apoptotic death and also inhibits potentially
UKfromcoronaryheartdisease(CHD),andthisaccountsforone protective autophagy.
thirdofalldeathsperannum.13Coronaryartery occlusion results TheprotectiveroleofSTAT3.Intheheart,STAT1andSTAT3
inthedeathofirreplaceablecardiacmyocytes(CM)byavarietyof haveasimilarinversefunctionalrelationshipastheydoincancer.
cell death mechanisms, including apoptosis, necrosis and Thus, in tumors, as in the heart, STAT1 is pro-apoptotic while
autophagy14 and many patients die from the acute effects of the STAT3isatumorpromoterandacardioprotectivefactor.Hearts
loss of functional CM. While the relative contribution of the frommicewithacardiac-specificknockoutofSTAT3havelarger
differentdeathmodalitiestotheoverallsizeoftheinfarctremains infarcts after I/R, with increased numbers of apoptotic CM,
debatable,considerableattentionhasrecentlybeendevotedtothe and these mice show greatly increased mortality.27 In addition,
apoptotic death of CM, since the molecular mechanisms of deletion of STAT3 in cardiomyocytes renders hearts more
theapoptoticpathwayarewellunderstoodandthereforeallowthe susceptible to inflammatory damage,28 such as that which
possibility of rational therapeutic intervention. accompanies I/R injury, especially after necrotic myocyte death.
The role of STAT1 in ischemic heart disease. Over 10 y ago, it STAT3 is also an essential component of the survivor activat-
wasdemonstratedthatischemia/reperfusion(I/R)injuryintherat ing factor enhancement (SAFE) pathway,29 an intrinsic protec-
heart led to STAT1 activation together with an increase in its tive signaling pathway that is paradoxically activated by TNFa
transcriptionalactivity,particularly onthepromoterofcaspase-1, in the heart at reperfusion. The SAFE pathway may also be
an enzyme important in the execution of apoptosis, and on both responsible for the observation that coronary effluents from a
Fas, a cell surface death receptor and its ligand FasL. Activated preconditioned heart confer protection and STAT3 activation in
STAT1 was colocalized with apoptotic CM, and STAT1 recipient hearts.30 Several cardioprotective agents have been
knockdown reduced I/R-induced cell death.15 These shown to activate STAT3, particularly on tyrosine, including
transcriptional effects required serine but not tyrosine cardiotrophin-1andtheurocortins,31opioids,32insulin,33leptin,34
phosphorylation,16 and the C-terminal STAT1 domain was erythropoietin,35 resveratrol and melatonin,36 though whether
sufficient to enhance I/R-induced apoptosis in CM.17 Since the STAT3activationisessentialfortheprotectivepropertiesofmost
C-terminus of STAT1 does not bind DNA and therefore cannot of these agents is unknown. Indeed, there is some evidence that
directly transactivate target genes, it must be acting as a the protective effects of erythropoietin are mediated via STAT5
coactivator. One possible interacting partner is the well-known (as well as STAT3)37,38
pro-apoptotic protein, p53, which has been implicated in the The downstream protective targets activated by STAT3 have
apoptosis ofCMfollowingI/R,18and STAT1has been shown to not been systematically investigated, although it is likely that at
enhance the transcriptional activity of p53 on pro-apoptotic least some of the changes in gene expression associated with
targets such as Bax.19 urocortin-mediatedprotectionaremediatedbySTAT3.39Inchick
OnemechanismbywhichSTAT1becomesactivatedfollowing embryo hearts, STAT3 has also been implicated in the activation
I/R is through free radicals, and it has been shown that the free of components of the reperfusion injury salvage kinase (RISK)
112 JAK-STAT Volume1Issue2
pathway, including PI3K, Akt, GSK3β and ERK2.40 Kinases of postconditionedpighearts.55ActivatedSTAT3activatestheRISK
the RISK pathway have been shown to inhibit opening of the pathway via PI3K, although, paradoxically, postconditioned
mitochondrial permeability transition pore (MPTP) during cardiac specific STAT3 knockout hearts also show protective
reperfusion41 and activation of the RISK pathway is induced by effects.56ThissuggeststhatactivationofSTAT3maybeone,but
severalcardioprotectiveagents,42suchasinsulin,whichisaknown nottheonlypathwayofRISKactivationinpostconditioning,and
STAT3 activator.33 Inhibition of MPTP opening has also been that other parallel initiators are also involved. Moreover,
shown to involve an interaction between mitochondrial STAT3 pharmacological inhibition of kinases involved in the RISK
and cyclophilin D.11 Metallothionein, an endogenous cardiopro- pathwaydidnotinhibittheprotectiveeffectsofpostconditioning
tective agent that acts as a free radical scavenger and a stabilizer in pigs.57 In contrast, another study has implicated the SAFE
of biomembranes, is also induced by STAT343 and may also pathway and demonstrated that TNFa is required for post-
contribute to its protective effects. conditioning. Indeed, TNFa itself can result in postconditioned
Ischemicconditioning.Theheartcanbeconditionedtobetter protection. Postconditioning by ischemia and TNFa both
tolerate a severe I/R injury by pharmacological and mechanical activate STAT3 and the postconditioning effects of TNFa
means, as well as by short non-lethal periods of I/R before are lost in STAT3-deficient hearts.58 Perhaps relevant in the
(preconditioning), during or after (postconditioning) a severe management of clinical myocardial infarction, postconditioning
lethal I/R episode (reviewed in ref. 44). Ischemic conditioning does not confer protection, nor result in STAT3 activation, in
does not even need to be applied to the heart itself, but is also depressed rats.59
cardioprotective when given to a distant organ or tissue such as Post-infarctionremodeling.Afteramyocardialinfarct,theleft
the intestine or a limb. However, preconditioning is clearly ventricle undergoes progressive anatomical changes in both the
academic in the clinical environment where patients can only infarcted and non-infarcted areas. In the infarcted area, thinning
receive medical intervention after myocardial infarction has of the ventricular wall occurs by a sliding movement of the
occurred. myocytes, termed “slippage,” and which mainly results from
The crucial role of STAT3 in ischemic preconditioning is degradation of collagen. Subsequently, cardiac fibroblasts deposit
underlinedbythefactthatmicewithacardiacspecificdeletionof new collagen fibers, resulting in scar formation. In the non-
STAT3cannotbepreconditioned.45STAT3activationisrequired infarctedarea,thereiscompensatoryhypertrophy;initially,thisis
for preconditioning in both normal46 and hypertrophic myocar- beneficial since it counteracts the functional deficit of the
dium,47 and involves IL-6/gp130 signaling (since IL-6 deficient infarcted area. However, over time, a hypertrophic myocardium
mice cannot be preconditioned), acting classically through becomes detrimental, since its increased oxygen demand cannot
JAK1/2 to produce tyrosine phosphorylation,48 and PKCε and befullysuppliedbythecompromisedventricle.Chronicmyocyte
the Raf-1/p42:44 MAPK pathway to induce serine phosphoryla- hypertrophy and death, together with interstitial fibrosis and an
tion.49 STAT1, STAT5 and 6 are also activated by ischemic inflammatory response lead inexorably to heart failure (reviewed
preconditioning,butthiswouldappearnottomediatethecardio- in ref. 60).
protective effects, since the increased phosphorylation of STAT5 The renin-angiotensin-aldosterone system. The renin-angiotensin
and 6 in the STAT3-deficient heart compared with wild-type (AT)-aldosterone system is one of the main mechanisms
hearts does not result in cardioprotection.50 However, remote implicated in heart failure following myocardial infarction. ATI,
preconditioningbyarmischemiainpatientsundergoingcoronary produced in the liver, is converted to ATII by AT-converting
bypasssurgery hasbeen showntoincreaseexpressionofactivated enzyme (ACE),and ATII,acting largely through the ATIItype I
STAT5 in the myocardium and to confer cardioprotection.51 receptor, induces myocyte apoptosis and hypertrophy and
There is also some evidence that cardioprotective agents such as promotes myocardial fibrosis (reviewed in ref. 61). ATII induces
urocortin,whichacts,atleastinpart,byactivationofSTAT3,can the rapid phosphorylation of STATs 1 and 2 with delayed
also precondition in the absence of brief ischemia.52 phosphorylation of STAT3,62 the activation of STAT3 being
Effectors of ischemic preconditioning downstream of activated mediated by a Rac-1-dependent mechanism.63 STAT5A and B
STAT3 include the kinase cascade of the RISK pathway.42 In are also rapidly phosphorylated by ATII, though their
addition, STAT3-mediated preconditioning is associated with phosphorylation is sustained for up to an hour.64
increased expression of known cardioprotective agents like In the remote non-ischemic area of rat hearts exposed to I/R,
COX-2 and HO-1, together with increases in anti-apoptotic thereisrapidphosphorylationofSTATs1,3,5Aand6,together
proteins that protect against both the intrinsic mitochondrial with JAK2 activation, and STATs 1, 3 and 5A remain activated
apoptoticpathway(Mcl-1,BclxL)andtheextrinsicdeathreceptor for up to 7 d post I/R. These activated STATs, and particularly
pathway (c-FLIP).53 STAT3 and STAT5A, have been shown to bind to the STAT
STAT3hasalsobeenimplicatedinischemicpostconditioning. consensus sequence in the angiotensinogen promoter, and may
Thus, postconditioning is associated with its increased tyrosine thus contribute to the continued activation of the autocrine
phosphorylation, and STAT3 and JAK2 inhibition both abolish ATII loop.65,66
the postconditioning protection. Moreover, mice with a cardiac The precise role of the individual STATs activated by ATII in
restricted STAT3deletion cannot bepostconditioned54andthere cardiac remodeling has not been fully elucidated. However,
is increased tyr705 phosphorylated STAT3 together with cardiac specific deletion of STAT3 is associated with the
increased Complex I respiration in mitochondria isolated from spontaneous development of heart failure in later life, and
www.landesbioscience.com JAK-STAT 113
STAT3 would appear to be particularly important in protecting dimerization upon binding of an IL-6 family ligand and signals
theheartfromdoxorubicin-inducedcardiomyopathy.67Moreover, through JAK-STAT and ERK1/2 pathways. Mice overexpressing
ATII also induces suppressor of cytokine signaling (SOCS)-3, bothIL-6anditsspecificreceptor,andinwhichthereistherefore
which associates with JAK-2 and inhibits activation of the constitutive activation of gp130, show sustained elevation of
JAK2-STAT1pathway,althoughtheeffectsofSOCS-3induction activated STAT3 and ventricular hypertrophy.71 There is also
on STAT3 signaling were not investigated in this model.68 In evidence that at least some of the hypertrophic effects of ATII
contrast, transgenic mice overexpressing STAT3 in the myo- may be mediated through the IL-6 family, since ATII has been
cardium have enlarged left ventricles with increased expression reported to increase expression of IL-6 itself, and of the family
of hypertrophic genes such as β myosin heavy chain as early as members leukemia inhibitory factor (LIF) and cardiotrophin-1
12 weeks of age.69 (CT-1) in cardiac fibroblasts.72 There is also increased expression
An alternative mechanism has been suggested for the ofbothIL-6andLIFinthehypertrophiedventriclesofratswitha
development of postpartum cardiomyopathy in female mice with hyperactiverenin-angiotensinsystemaswellasintheventriclesof
acardiacmyocyte-specificdeletionofSTAT3.70Here,theactivity spontaneously hypertensive rats.73 However, the increased
and expression of cathepsin D is increased, resulting in the expression of CT-1 in failing hearts is accompanied by reduced
generation of an angiogenic and proapoptotic form of prolactin. gp130 expression,74suggesting thatthere maybeacompensatory
Correspondingly, inhibition of prolactin with bromocriptine mechanism inhibiting overactivation of gp130 signaling. In
prevents the development of the cardiomyopathy. cultured cardiomyocytes, both LIF and CT-1 induce a
Gp130 signaling. The pro-hypertrophic effects of STAT3 are hypertrophic response, which in both cases is mediated by
reinforced by studies on the effects of the interleukin (IL)-6 activated STAT3.31,75 Deletion of Shp2, an SH2 domain
family of cytokines and their receptors. Receptors for the IL-6 containing tyrosine phosphatase that is known to dephos-
family consist of a specific ligand binding subunit and a shared phorylate Tyr705 of STAT3,76 also leads to enhanced STAT3
non-ligand binding transducer, gp130, which undergoes activation and cardiomyopathy.77
Figure1.STAT1(ST1)andSTAT3(ST3)regulatetranscriptionalprocessesandhaveopposingrolesinischemicpathology,withST1activation
contributingtocelldeathsignals,whileST3activitylargelymediatescytoprotectivesignals.
114 JAK-STAT Volume1Issue2
Concluding Remarks phenotype, and their precise role needs to be more carefully
investigated.
Although all seven STATs have been described in the mouse Anotherareathathasreceivedonlylimitedattentioniswhether
heart,78 studies on the role of STATs in cardiac physiology and bothTyrandSerphosphorylationarerequiredforSTATactivity
pathology have largely been restricted to STAT1 and STAT3. In in the heart, although there is evidence that Ser phosphorylation
particular, strong evidence suggests that these two STATs play aloneissufficienttoallowdeathsignalingbySTAT1.16Moreover,
essentially antagonistic roles in ischemic pathology, with STAT1 transcription factors generally do not act in isolation, but their
activationcontributingtodeathsignals,andSTAT3largelybeing activity is modulated by other coactivators and corepressors,
protective (Fig.1). Prolonged STAT3 activation, however, is another area that remains to be systematically investigated in the
strongly implicated in the post-infarction changes leading to heart.
ventricularhypertrophyandheartfailure.STAT1andSTAT3can Nevertheless,sufficientevidencehasaccumulatedtoemphasize
formheterodimers,andwhetherthisoccursinthecardiacsetting, the important role of the JAK-STAT pathway in ischemic heart
and how heterodimerization modulates the activities of STAT1 disease. However, further insights into the complexities of the
and STAT3 homodimers remains unclear. There are also system are clearly required before we can begin to make
suggestionsthatotherSTATsmayalsocontributetotheischemic translational predictions that are other than simplistic.
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