initially uncovered by experiments aimed at understanding ifn and ifn- induced transcriptional activation , a new pathway of signal transduction from the cell surface to genes in the nucleus has been recognized in last decades of 19th century . the pathway is called the jak - stat pathway . similar to other pathways , association of ligands to their receptors leads to activation of one of the jak family of tyrosine kinases associated with a trans - membrane receptor , and subsequently leads to the phosphorylation on tyrosine of one or more of a family of latent cytoplasmic transcription factors called stats . these latter proteins perform a dual role , first as signal transducers by acting as substrates of the jaks , and after phosphorylation and nuclear translocation , by acting as transcriptional activators . while ifn and ifn were the first polypeptide ligands described that trigger this pathway , it is now known that many other ligands such as il-6 family cytokines , il-10 and neurohormones can also activate proteins in the pathway . the details of early experiments in hematopoietic and other systems with the ifns and cytokines have been summarized in many decent reviews ; however , its cardiovascular responses are still limited in literature . in current review , we will mainly discuss the critical role of stat pathway in cardiovascular diseases . seven stats ( stats 1 , 2 , 3 , 4 , 5a , 5b and 6 ) have been identified in mammals and range in size from 750 to 900 amino acids . the structural and functional analysis of these proteins suggests that they have six conserved domains ( fig .  1 ) . this includes the n - terminal domain ( nh2 ) , the coiled - coiled domain ( ccd ) , the dna binding domain ( dbd ) , the linker domain and the sh2/tyrosine activation domain . in contrast , the carboxyl - terminal transcriptional activation domain ( tad ) is quite divergent and contributes to stat specificity ( fig .  1 ) . the four core domains contact each other by large inter - domain interfaces , suggesting that structural changes induced in one domain may also affect other domains . the identification of stat homologs in simpler eukaryotes suggests that this family arose from a single gene . n - terminal domain ; coiled  coil domain ( ccd ) ; dna binding domain ( dbd ) ; linker domain ; src homology domain 2 ( sh2 ) and the tyrosine residue ( y ) phosphorylation sites . the n - terminal half of the protein ( ~125 amino acids ) consists of two relatively poorly characterized domains . this domain is well conserved between these families of protein and is reported to promote cooperativity in dna binding and to regulate nuclear translocation . it represents an independently folded and stable moiety , which can be cleaved from the full - length molecule by limited proteolysis . several studies suggest that n - terminal dimerization promotes cooperativity of binding to tandem gas ( ifn activated sequences ) elements . other studies have suggested that the n - terminal stat domain promotes interaction with the other proteins or receptors and that it regulates nuclear translocation . the coiled - coil domain ( amino acids ~135 to ~315 ) consists of a four - helix bundle that protrudes about 80  laterally from the core structure . many studies have also implicated the coiled - coil domain in receptor binding and tyrosine phosphorylation in addition to nuclear export . the dna - binding domain ( dbd ; amino acids ~320 to ~500 ) recognizes members of the -activated sequence ( gas ) family of enhancers and ( like the upstream coiled - coil domain ) appears to regulate nuclear export . the adjacent linker domain ( amino acids ~500 to ~600 ) is important in assuring the appropriate structure of the dna - binding motif and also appears to regulate nuclear export in resting cells . not surprisingly , the sh2 domain ( amino acids ~600 to ~700 ) is the most highly conserved motif and mediates both receptor - specific recruitment and stat dimerization . the number of direct contact sites between amino acid residues and dna are modest , accounting for a dissociation constant in the nanomolar range . thus , cooperativity in dna binding is likely to be important in effective transcriptional activity . all of these proteins ( stat16 ) except stat2 are known to homodimerize in vivo . dimerization requires the binding of a phosphorylated tyrosine activation motif on one stat subunit to the sh2 domain of the other subunit . finally , the carboxyl - terminus carries a transcriptional activation domain ( tad ) , which is conserved between homologs ( e.g. , murine and human ) . however , the carboxyl - terminus varies considerably in both length and sequence between different stat family members . once again , stat2 is an exception , since its tad sequence diverges considerably between the murine and human homologs . as a part of normal cytokine signaling cascade , the jak - stat pathway is also initiated by binding of a ligand to its receptor in the plasma membrane and the subsequent homo- or heterodimerization of the receptor . in the heart , il-6 , il-11 , leukemia inhibitory factor ( lif ) , oncostatin m , ciliary neurotrophic factor ( cntf ) and cardiotrophin - like cytokine ( ct-1 ) are the major cytokines that transduce their signals via glycoprotein 130 ( gp130 ) predominantly to stat3 and 5 . the receptor dimerization , in turn , induces phosphorylation and activation of jak proteins , which are associated with the intracellular domain of the receptor . jak proteins phosphorylate the receptor , thereby creating docking sites for cytosolic stat proteins via their sh2 domains . subsequently , stat proteins become phosphorylated on a specific tyrosine residue ( for example , tyr705 for stat3 ) by activated jak kinases , and undergo homo- or heterodimerization by interaction of the phosphotyrosine residue of one stat monomer and the sh2 domain of the other monomer . once dimerized , these proteins dissociate from the receptor and translocate into the nucleus , where they bind to specific dna sequences and regulate the expression of target genes ( fig .  2 ) . in the heart , stat proteins regulate the expression of genes encoding proteins mainly involved in inflammation , cellular signaling , apoptosis , angiogenesis and extracellular matrix composition . the phosphorylation of an additional specific serine residue in the transactivation domain of stat proteins ( ser727 for stat3 ) generally promotes transcriptional activity . the activation and nuclear translocation of stats usually occurs within 15 min , but stat proteins are also rapidly inactivated , resulting in a half - life of nuclear phosphorylated stat between 15 and 30 min . upon de - phosphorylation by nuclear phosphatases , the jak - stat pathway is not only controlled via phosphorylation of the signaling proteins , but also by negative regulators . upon activation , stats bind to the promoter region of socs genes ( suppressors of cytokine signaling ) and upregulate the transcription of these target genes ( fig .  2 ) . socs proteins ( mainly socs 1 and 3 ) negatively regulate the jak - stat pathway by either directly binding to jak , by binding to the receptor and to jak , or by competing with stats for the docking sites at the receptor . another negative feedback mechanism of the jak / stat pathway comprises shp-2 proteins ( src homology 2 domain containing protein tyrosine phosphatase ) , which dephosphorylate the receptor , jak or stat proteins . the details of the canonical jak - stat signaling pathway have been extensively reviewed elsewhere . these include animal s species , cell type differences and its intra - cellular distribution . figure  2 . a putative model for jak - stat signaling pathway . upon binding ligand ( il-10 ) , activated stat3 is released from the receptor , dimerize , translocate to the nucleus , and bind with transcription factors to regulate expression of many cardio - protective , anti - inflammatory or growth related genes . as a feedback loop it also regulates expression of suppressor of cytokines signaling genes ( socs ) . in addition to jaks , ptks and mapk , activated by ang ii , may participate in phosphorylation of stat3 . activated stat3 translocate to the nucleus to activate genes , such as c - fos , c - myc , 2-macroglobulin and tissue inhibitor metalloproteinase-1 ( timp-1 ) by binding to the sis - inducible element ( sie ) of the promoter . seven stats ( stats 1 , 2 , 3 , 4 , 5a , 5b and 6 ) have been identified in mammals and range in size from 750 to 900 amino acids . the structural and functional analysis of these proteins suggests that they have six conserved domains ( fig .  1 ) . this includes the n - terminal domain ( nh2 ) , the coiled - coiled domain ( ccd ) , the dna binding domain ( dbd ) , the linker domain and the sh2/tyrosine activation domain . in contrast , the carboxyl - terminal transcriptional activation domain ( tad ) is quite divergent and contributes to stat specificity ( fig .  1 ) . the four core domains contact each other by large inter - domain interfaces , suggesting that structural changes induced in one domain may also affect other domains . the identification of stat homologs in simpler eukaryotes suggests that this family arose from a single gene . n - terminal domain ; coiled  coil domain ( ccd ) ; dna binding domain ( dbd ) ; linker domain ; src homology domain 2 ( sh2 ) and the tyrosine residue ( y ) phosphorylation sites . the n - terminal half of the protein ( ~125 amino acids ) consists of two relatively poorly characterized domains . this domain is well conserved between these families of protein and is reported to promote cooperativity in dna binding and to regulate nuclear translocation . it represents an independently folded and stable moiety , which can be cleaved from the full - length molecule by limited proteolysis . several studies suggest that n - terminal dimerization promotes cooperativity of binding to tandem gas ( ifn activated sequences ) elements . other studies have suggested that the n - terminal stat domain promotes interaction with the other proteins or receptors and that it regulates nuclear translocation . the coiled - coil domain ( amino acids ~135 to ~315 ) consists of a four - helix bundle that protrudes about 80  laterally from the core structure . many studies have also implicated the coiled - coil domain in receptor binding and tyrosine phosphorylation in addition to nuclear export . the dna - binding domain ( dbd ; amino acids ~320 to ~500 ) recognizes members of the -activated sequence ( gas ) family of enhancers and ( like the upstream coiled - coil domain ) appears to regulate nuclear export . the adjacent linker domain ( amino acids ~500 to ~600 ) is important in assuring the appropriate structure of the dna - binding motif and also appears to regulate nuclear export in resting cells . not surprisingly , the sh2 domain ( amino acids ~600 to ~700 ) is the most highly conserved motif and mediates both receptor - specific recruitment and stat dimerization . the number of direct contact sites between amino acid residues and dna are modest , accounting for a dissociation constant in the nanomolar range . thus , cooperativity in dna binding is likely to be important in effective transcriptional activity . all of these proteins ( stat16 ) except stat2 are known to homodimerize in vivo . dimerization requires the binding of a phosphorylated tyrosine activation motif on one stat subunit to the sh2 domain of the other subunit . finally , the carboxyl - terminus carries a transcriptional activation domain ( tad ) , which is conserved between homologs ( e.g. , murine and human ) . however , the carboxyl - terminus varies considerably in both length and sequence between different stat family members . once again , stat2 is an exception , since its tad sequence diverges considerably between the murine and human homologs . as a part of normal cytokine signaling cascade , the jak - stat pathway is also initiated by binding of a ligand to its receptor in the plasma membrane and the subsequent homo- or heterodimerization of the receptor . in the heart , il-6 , il-11 , leukemia inhibitory factor ( lif ) , oncostatin m , ciliary neurotrophic factor ( cntf ) and cardiotrophin - like cytokine ( ct-1 ) are the major cytokines that transduce their signals via glycoprotein 130 ( gp130 ) predominantly to stat3 and 5 . the receptor dimerization , in turn , induces phosphorylation and activation of jak proteins , which are associated with the intracellular domain of the receptor . jak proteins phosphorylate the receptor , thereby creating docking sites for cytosolic stat proteins via their sh2 domains . subsequently , stat proteins become phosphorylated on a specific tyrosine residue ( for example , tyr705 for stat3 ) by activated jak kinases , and undergo homo- or heterodimerization by interaction of the phosphotyrosine residue of one stat monomer and the sh2 domain of the other monomer . once dimerized , these proteins dissociate from the receptor and translocate into the nucleus , where they bind to specific dna sequences and regulate the expression of target genes ( fig .  2 ) . in the heart , stat proteins regulate the expression of genes encoding proteins mainly involved in inflammation , cellular signaling , apoptosis , angiogenesis and extracellular matrix composition . the phosphorylation of an additional specific serine residue in the transactivation domain of stat proteins ( ser727 for stat3 ) generally promotes transcriptional activity . the activation and nuclear translocation of stats usually occurs within 15 min , but stat proteins are also rapidly inactivated , resulting in a half - life of nuclear phosphorylated stat between 15 and 30 min . upon de - phosphorylation by nuclear phosphatases , stat proteins shuttle back into the cytosol via the nuclear pore . the jak - stat pathway is not only controlled via phosphorylation of the signaling proteins , but also by negative regulators . upon activation , stats bind to the promoter region of socs genes ( suppressors of cytokine signaling ) and upregulate the transcription of these target genes ( fig .  2 ) . socs proteins ( mainly socs 1 and 3 ) negatively regulate the jak - stat pathway by either directly binding to jak , by binding to the receptor and to jak , or by competing with stats for the docking sites at the receptor . another negative feedback mechanism of the jak / stat pathway comprises shp-2 proteins ( src homology 2 domain containing protein tyrosine phosphatase ) , which dephosphorylate the receptor , jak or stat proteins . the details of the canonical jak - stat signaling pathway have been extensively reviewed elsewhere . these include animal s species , cell type differences and its intra - cellular distribution . figure  2 . a putative model for jak - stat signaling pathway . upon binding ligand ( il-10 ) , activated stat3 is released from the receptor , dimerize , translocate to the nucleus , and bind with transcription factors to regulate expression of many cardio - protective , anti - inflammatory or growth related genes . as a feedback loop it also regulates expression of suppressor of cytokines signaling genes ( socs ) . in addition to jaks , ptks and mapk , activated by ang ii , may participate in phosphorylation of stat3 . activated stat3 translocate to the nucleus to activate genes , such as c - fos , c - myc , 2-macroglobulin and tissue inhibitor metalloproteinase-1 ( timp-1 ) by binding to the sis - inducible element ( sie ) of the promoter . all seven stat family members have been reported to be expressed in the heart and/or cultured cardiac myocytes , fibroblasts and endothelial cells . at cellular compartment level , stat localization is not restricted to the cytosol and the nucleus but recently , stat proteins have also been identified in mitochondrial fraction . as for the exact role of jak - stat signaling in cardiac function and diseases , most of the available information relates to stat1 and 3 family members . various stimuli which activate hypertrophic growth of cardiac myocytes and/or provide cardio - protection have been demonstrated to activate jak - stat signaling in the heart . importantly , studies have established that these stimuli also enhance cardiac stat functional activity , as assessed by electrophoretic mobility shift assays of dna binding activity , or promoter - reporter assays of transcriptional activity . mechanical stretch and pressure over - load , myocardial infarction and ang ii treatment has been shown to activate cardiac jak - stat signaling . in addition , ischemia and ischemia / reoxygenation also activates jak - stat signaling in cultured ventricular myocytes , isolated heart preparations or the in situ hearts . it has been well documented that monocytes and macrophages produce inflammatory cytokine to repair the injury during myocardial infarction and hypertrophy . angiotensin ii also mimics the action of cytokines by activation of tissue inhibitor of metalloproteinase-1 ( timp-1 ) , an important factor associated with cardiac remodeling . the mechanisms whereby g - protein receptors couple to tyrosine phosphorylation in general and more specifically to the jak - stat pathway , are not yet clearly elucidated . previously , it was suggested that yxxq regions of at1 receptors could serve as a docking sites to facilitate stat3 phosphorylation . alteration in jak - stat signaling pathways were also reported in patients with end - stage dilated cardiomyopathy . the early activation of stat3 during diseased stage could be the protective response of system to reduce the cardiac death and remodeling . recent reports have shown that transgenic mice with global deletion of stats are embryonically lethal further suggesting its role in development and growth . to sidestep the embryonic lethal phenotype of global stat3 knockout mice and to better understand the rle of stat3 in the heart cardiac myocytes - specific stat3 ko mice have been developed . these mice are significantly more susceptible to cardiac injury under the influence of various stress signals suggesting a protective role of stat3 in heart . however , a major disadvantage of these tissue specific stat3-ko mice is the pathological phenotype , which develops with age and thus limits the direct assessment of the role of stat3 in cardio - protection . recently , bolli and coworkers generated inducible , cardiac myocyte - specific stat3-deficient mice , which are of great value since they overcome the problems of embryonic lethality and the consequences of chronic alterations in stat3-dependent gene expression . these mice excluded the possibility of age - dependent alterations in apoptosis , fibrosis , capillary density , and cardiac function , and importantly these mice did not show age dependent cardiac hypertrophy or dilatation . therefore , the inducible cardiac myocyte - specific stat3-ko mouse represents a novel and attractive model to study the role of stat3 in the cardio - protection by ischemic pre- and post - conditioning without the confounding effects associated with chronic stat3 deletion . mechanism for cardio - protective action of stat3 is not well studied in cardiovascular diseases . mostly , the protective effect of stat3 in the heart is linked to the reduction in inflammation . evidence for this notion comes from the studies in which stat3-deficient mice treated with lipopolysaccharide ( lps ) demonstrated significantly more apoptosis and fibrosis than their wt counterparts . furthermore , stat3 ko cardiac myocytes secrete significantly more tumor necrosis factor  ( tnf ) in response to lps than those with wt stat3 . the anti - inflammatory and anti - fibrotic effects of stat3 could be due to direct transcriptional inhibition of nuclear factor kappa - b ( nfb ) . indirectly , we have also shown that use of il-10 , an anti - inflammatory pleotropic cytokines , markedly activated stat3 phosphorylation after myocardial infarction injury and thus improve heart function . many recent studies indicated that stat3 induces the expression of pro - angiogenic factors from resident cardiac cells . it has been shown that overexpression or activation of stat3 in cardiac myocytes enhances vegf expression , which , in turn , promotes myocardial capillary formation . cardiac myocyte - specific deletion of vegf reduces coronary microvascularization , suggesting that vegf may be an important target gene mediating pro - angiogenic effects of stat3 . a recent interesting study reported that stat3 plays a critical role during pregnancy related adaptive cardiac hypertrophy by activation of angiogenesis ( increased vegf ) and by inhibition of oxidative stress ( increased mnsod level ) . in our previous report we documented that il-10 markedly increase the vegf and capillary beds in infarct zone after myocardial infarction . this effect of il-10 on microvasculature is stat3-dependent as stat3 inhibitor markedly eliminated the il-10 responses . in contrast , other groups have shown stat3 does not affect the expression of vegf . using stat3 ko animals they reported that vegf expression is unaffected by stat3 deletion although these animals showed compromised heart function and reduced angiogenesis after myocardial infarction . interestingly , stat3 ko animals showed increased expression of connective tissue growth factor ( ctgf ) , plasminogen activator inhibitor 1 ( pai-1 ) , tissue inhibitor of matrix metalloproteinase 1 ( timp1 ) and thrombospondin 1 ( tsp1 ) compared with wt mice after mi . all these factors are potent suppressor of angiogenesis as well as activator of fibroblast proliferation . in addition , the increased fibrosis and myocyte cell loss might be due to reduced blood and thus oxygen supply to the heart cells in this model . recently we found that endothelial progenitor cells ( epcs ) can also play critical role in neovascularization in heart . during ischemic condition ( in mi model ) both homing and survival of epcs in the heart was markedly reduced . in this fascinating study we have shown that during myocardial infarction the mobilization of epcs from bone marrow ( bm ) to heart is impaired and contributes to diminished angiogenesis and markedly reduced left ventricular functions . we also found that modulation of inflammation il-10 therapy markedly improves epcs survival and neovascularization in the border zone of the infarct . interestingly , il-10 dependent increase in epcs survival and function is partially dependent on stat3 signaling , at least in in vitro system . in addition , we also showed that differentiation of functional cardiac myocytes from pluripotent embryonic stem cells ( es ) under the influence of cytokines and growth factors requires stat3 activity . in this study use of selective stat3 inhibitor , markedly reduced the leukemia inducing factor ( lif ) and bone morphogenic protein 2 ( bmp-2 ) induced cardiac myocytes differentiation from murine es cells . in addition , sdf1/cxcr signaling is critical for the homing of progenitor cells from bone marrow to the heart for cardiac repair during heart failure . recently it has been shown that inhibition of stat3 ( both pharmacological and genetic knockdown ) significantly abolished the sdf1/cxcr1 mediated cardiac protection during ischemia / reperfusion injury . another pertinent mechanism for cardio - protective action of stat3 is by reducing stress - induced cell death in heart as apoptosis is one of the hallmarks of heart failure . hydrogen peroxide ( a potent cell death activator ) treated neonatal rat ventricular myocytes ( nrcm ) showed reduced expression of phosphorylated stat3 . in isolated rat hearts , perfused with ag-490 ( potent jak1/stat3 inhibitor ) enhanced the number of apoptotic cardiac myocytes . the anti - apoptotic function of stat3 was also confirmed in mice with a cardiac myocyte - specific deletion of stat3 . these mice showed higher ischemia / reperfusion - induced apoptosis compared with wild type control . furthermore , the stat3-dependent transcriptional upregulation of anti - apoptotic and cyto - protective proteins ( bcl - xl , hsp70 and mnsod ) clearly demonstrated the critical role of stat3 in cardiac myocytes survival . although early activation of stat3 is well established during ischemia / reperfusion ( i / r ) , its transcriptional regulation is probably too slow a process to provide the immediate rescue from cell death during early minutes of reperfusion . recently , stat3 has been identified in cardiac myocyte mitochondria , and its pharmacological inhibition or genetic ablation impaired complex i respiration and calcium retention capacity . conversely , a mitochondrial - targeted stat3 overexpression in mice preserved complex i respiration during simulated ex vivo ischemia and reduced the formation of reactive oxygen species . these studies suggest that a pool of stat3 resides in the mitochondria and try to inhibit ros production by inhibition of complex i and ii activity . evidence for this notion comes from the study where cardiac myocytes specific overexpression of transcriptionally inactive mitochondrial stat3 in transgenic mice hindered the ischemia - induced mitochondrial complete complex i and ii activity , cytochrome c release and ros production . recent studies , using pharmacological inhibitors , have demonstrated that ischemic post - conditioning preserve mitochondrial complex 1 respiration both in vivo and in vitro . the exact phosphorylation site that is important for the improvement in mitochondrial function by stat3 is not clear but may vary with species : in mouse cardiac myocyte mitochondria serine727 site , whereas both the serine727 and the tyrosine705 site in rat cardiac myocyte mitochondria and only the tyrosine705 site in pigs is deemed important . the increased stat3 phosphorylation at tyrosine705 was associated not only with better preservation of complex 1 respiration but also with improved calcium retention capacity as a measure of mitochondrial permeability transition pore inhibition . the cardio - protective action of stat3 is also partially dependent on the age of animals . in a recent study it has been demonstrated that the beneficial effects of ischemic post - conditioning is lost in aged animals and suggested that reduced stat3 levels may be cause of this effect . interestingly , in contrast to the cardio - protective nature of active stat3 , some recent studies also suggested that the un - phosphorylated stat3 can induce adverse cardiac remodeling . during chronic stress the signals from at1r leads to unregulated expression of stat3 resulting in excessive accumulation of un - phosphorylated stat3 into the nucleus where they can bind with target gene ( such as p300/cbp ) promoters thereby inducing genes that are involved in adverse heart function . it is believed that the normal mechanisms of stat clearance from nucleus is impaired during chronic stress pathology and thus contribute toward the accumulation of u - stat3 . moreover , u - stats have been shown to partner with nfb p65 and irf1 in binding to different hybrid dna elements . hence , u - stat3 may partner with different factors depending on the cell type and sequence context , thereby regulating constitutive gene expression both positively and negatively . many investigators believe that stats signaling might be detrimental and induce distractive signaling in heart , however , we and others published data indicating that stat3 mediates cardio - protective signaling . stat3 activation is important for facilitating protective effects in the heart such as compensatory hypertrophy or a reduction in apoptosis . additionally , as mentioned above stat3 activation is central for the cardio - protection by ischemic pre- and post - conditioning . stimulation of stat3 activity is expected to be beneficial during the transition from compensated hypertrophy to heart failure . agonist induced activation of stat signaling in the myocardium could be a potential strategy to induce cardio - protective signaling . however , stats as transcriptional activators or co - activators control the transcription of many target gene and excessive activation of some genes might be detrimental . for example , il-6 mediated excessive activation of inos gene increased stat3-dependent nitric oxide synthesis and decreases cardiac contractility . therefore , the stat3 activation in cardiovascular disease must be carefully controlled and well defined treatment strategies aiming for a balanced stat3 signaling should be developed in order to protect the heart from pathophysiological stress . in conclusion , stat signaling is an important mechanism in the protection of cardiac cells from different stress . to understand the mechanisms and inhibit the transition of adaptive hypertrophy to maladaptive hypertrophy , stat signaling could play an important role , as it gets activated during physiological hypertrophy and inhibited in chronic pathological conditions . basic and translational studies should be focused toward understanding the factors / stimuli that regulate stat activity at late stage of diseases . another area of research that should make a significant stride in the next few years is to generate safer agonists and carrier molecules that can be given to patients with an end - stage disease condition to improve heart function .
in cardiac and many other systems , chronic stress activates avfamily of structurally and functionally conserved receptors and their downstream signaling molecules that entail tyrosine , serine or threonine phosphorylation to transfer the messages to the genetic machinery . 
 however , the activation of the janus kinases ( jaks ) and their downstream signal transducer and activator of transcription ( stats ) proteins is both characteristic of and unique to cytokine and growth factor signaling which plays a central role in heart physiology . 
 dysregulation of jak - stat signaling is associated with various cardiovascular diseases . 
 the molecular signaling and specificity of the jak - stat pathway are modulated at many levels by distinct regulatory proteins . here 
 , we review recent studies on the regulation of the stat signaling pathway that will enhance our ability to design rational therapeutic strategies for stress - induced heart failure .