Associate editor: O. Binah
Many good reasons to have STAT3 in the heart

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Abstract

The transcription factor signal transducer and activator of transcription 3 (STAT3) participates in a wide variety of physiological processes and directs seemingly contradictory responses, such as proliferation and apoptosis. The constitutive activation of STAT3 promotes tumor growth and angiogenesis and is associated with drug resistance in cancer therapy. In contrast, in the heart, the down-regulation of STAT3 has been associated with end-stage heart failure in patients. Moreover, multiple studies showed that the activation of STAT3 promotes cardiomyocyte survival and hypertrophy, as well as cardiac angiogenesis, in response to various pathophysiologic stimuli, strongly suggesting that STAT3 is beneficial for the heart. Conditional knockout (STAT3-KO) mice harboring a cardiomyocyte-restricted deletion of STAT3 showed enhanced susceptibility to cardiac injury caused by myocardial ischemia, systemic inflammation, or drug toxicity. STAT3-KO mice were also more prone to the pathogenesis of age-related heart failure. Thus, STAT3 is involved in multiple mechanisms required for the protection of the heart from injury and heart failure. These observations should be taken into account in designing novel therapeutic strategies for the prevention of cardiac failure.

Introduction

Signal transducer and activator of transcription 3 (STAT3) is a member of a structurally related protein family (STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6), having a conserved amino terminus involved in tetramerization, a DNA binding domain with a sequence specificity for a palindromic interferon (INF)-γ activated sequence (GAS), and an SH2 domain involved in receptor recruitment as well as STAT dimerization, and a carboxy-terminal transactivation domain. Although STAT proteins are structurally related, recent studies with genetically manipulated mice suggested a high degree of specificity for the various STAT proteins. Mice lacking one or more STAT proteins have shown relatively discrete phenotypes, assigning each STAT protein to specific pathways and functions (reviewed by Levy & Lee, 2002). Not so with STAT3. Unlike all other members of the STAT gene family, the functional analysis of STAT3 in vivo is complicated by the fact that conventional targeted deletion of STAT3 results in early embryonic lethality (Takeda et al., 1997). This finding implied that STAT3 might be more generally deployed (Hirano et al., 2000, Takeda & Akira, 2001). In fact, conditional knockout mice have demonstrated pleiotropic requirements of STAT3 in many organs and cell types, including the heart.

STAT3 is activated by numerous growth factors and cytokines, most notably by the interleukin-6 (IL-6) cytokine family (e.g., IL-6), leukemia inhibitory factor (LIF), and cardiotrophin-1 (CT-1), which signal through the shared receptor glycoprotein 130 (gp130; Fig. 1; Heinrich et al., 1998, Aaronson & Horvath, 2002). Upon receptor activation, STAT3 phosphorylation (at tyrosine 705) is mediated by Janus kinases, JAK1 or JAK2. This activation of STAT3 is required for dimerization with itself or other STAT proteins, nuclear translocation, and DNA binding (reviewed by Levy & Lee, 2002). A second phosphorylation site at serine 727 (S727) is possibly induced by mitogen activated kinases (MAPK) ERK1/2, p38, and Jun kinase (JNK) and seems to influence the transcriptional activation of STAT3 (Levy & Lee, 2002). In normal cells, STAT3 activation is transient and tightly controlled, for example, by negative feedback mechanisms. Among these, STAT3-mediated up-regulation of the suppressor of cytokine signaling (SOCS) proteins block STAT3 activation by binding to cytokine receptors and thereby blocking JAKs and by promoting the ubiquitination and degradation of the JAK/receptor complex. In addition, STAT3 induces also the expression of protein inhibitors of activated STATs (PIAS), which are proteins that physically interact with STAT3 and block DNA binding and transcriptional activity of STAT3 transcription factors complexes (reviewed by Heinrich et al., 2003). Alterations in STAT3 activation are associated with various pathophysiological processes, for example, permanent down-regulation of STAT3 in cardiomyocytes results in heart failure (Jacoby et al., 2003, Podewski et al., 2003, Hilfiker-Kleiner et al., 2004). In contrast, the constitutive activation of STAT3 promotes tumor growth (Turkson, 2004).

In this review, we summarize alterations of STAT3 in human failing hearts, as well as cardiac responses associated with the modulation of STAT3 expression and activity. Notably, cardiomyocyte STAT3 activity is required for controlling cardiac growth, function, tissue architecture, and protection against cardiovascular stress. Moreover, we discuss STAT3 as a therapeutic target in both heart failure and cancer therapy.

Section snippets

Altered regulation of the transcription factor signal transducer and activator of transcription 3 in failing hearts

Dilated cardiomyopathy (DCM) represents a common end-stage disease state of the myocardium in response to different environmental and genetic factors, a fact that has led to the proposition of shared signaling pathways for cardiac dilation and failure (Hunter & Chien, 1999). A growing body of evidence indicates that IL-6-related cytokine signaling via the shared receptor gp130 provides a critical myocyte survival pathway in vivo. Most notably, gene targeted mice with a cardiomyocyte-restricted

The transcription factor signal transducer and activator of transcription 3 promotes survival and hypertrophy in cardiomyocyte in vitro

Various studies have shown that STAT3 plays an essential role for cardiomyocyte hypertrophy (Fig. 1; Kunisada et al., 1998). Moreover, it has been shown that STAT3 exerts direct cytoprotective effects in cardiomyocytes subjected to ischemia or toxic stress (Fig. 1; Kunisada et al., 2000, Negoro et al., 2001). In this regard, the hypertrophic and cytoprotective effects of LIF could be assigned to STAT3. More specifically, LIF-induced protection of cardiomyocytes from intracellular reactive

The role of the transcription factor signal transducer and activator of transcription 3 in the postnatal heart

The systemic disruption of STAT3 results in growth defects and the absence of mesoderm formation, causing early embryonic lethality, which demonstrates a crucial role of STAT3 in the embryonic development (Takeda et al., 1997). In contrast, mice harboring a cardiomyocyte specific knockout of STAT3 (STAT3-KO, Fig. 2A), deleting STAT3 in the heart around birth, are born according to Mendelian inheritance ratios, survive into adulthood, and do not show cardiac dysfunction up to the age of 3 months

The transcription factor signal transducer and activator of transcription 3 regulates postnatal angiogenesis and homeostasis of extracellular matrix in the heart

Postnatal growth of the heart is accompanied by a proportional growth of the capillary network (Hudlicka & Brown, 1996). Paracrine factors from cardiomyocytes have been postulated to play a pivotal role in this process (Dor et al., 2002). The observation that the loss of STAT3 in cardiomyocytes leads to reduced capillarization and alterations in interstitial fibrosis in the heart suggests an important role of STAT3 in controlling paracrine mechanisms involved in postnatal angiogenesis and

Role of the transcription factor signal transducer and activator of transcription 3 in the pathophysiology of heart failure

Mice lacking gp130 develop dilated cardiomyopathy and cardiomyocyte apoptosis when subjected to pressure overload (Hirota et al., 1999). This was associated with a loss of STAT3 phosphorylation, suggesting that gp130 acting via STAT3 might be a critical survival signaling pathway in the heart (Hirota et al., 1999). The pharmacological inhibition of the JAK/STAT pathway by AG490, a JAK2 inhibitor, prevented the activation of STAT3 and enhanced myocardial injury after infarction, further

Controversial views: transcription factor signal transducer and activator of transcription 3, a primary target in cancer drug therapy and in heart failure?

In normal cycling cells, STAT3 signaling is tightly controlled to maintain standard cellular responses. In contrast, persistent STAT3 activation is frequently associated with malignant transformation, and it is well established that constitutively active STAT3 is one of the causative molecular abnormalities in oncogenesis (reviewed by Turkson, 2004). Aberrant STAT3 activation is known to promote uncontrolled growth and survival through the dysregulation of gene expression, including cyclin D1,

Conclusion

In our current understanding, STAT3 signaling appears to be a key player in the protection of the heart against pathophysiological stress, such as ischemia, mechanical stress, and cytotoxic agents. In future studies, the biological roles of STAT3 in the heart should be further explored, with the aim to define STAT3 or downstream mediators as prime targets for novel therapies to treat heart failure or to protect the heart from unwanted drug-related side effects. In turn, novel therapeutic

Acknowledgments

The original work reported here was supported by the Deutsche Forschungsgemeinschaft, the Jean Leducq Foundation, and the Italian Ministry of University and Research.

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