Skip to main content
SpringerLink
Log in

The STAT3 Pathway and Downstream Mechanisms in Cardiac Remodeling: Friend or Foe

  • Chapter
  • First Online:
Book cover Cardiac Remodeling

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 5))

Abstract

Multiple in vitro and in vivo studies have shown that the signal transducer and activator of transcription 3 (STAT3) protein regulates key mechanisms in cardiac physiology (exercise, pregnancy) and pathophysiology (pressure overload, ischemia/reperfusion, myocardial infarction (MI), myocarditis, and cardiotoxic agents). STAT3 is activated in various cardiac cell types including cardiomyocytes, endothelial cells, fibroblasts, and cardiac progenitor cells by a multitude of factors including cytokines, growth factors, neurohormones, mechanical load, and ischemia. It acts as a signaling molecule, a transcription factor, and a mitochondrial protein involved in energy production, and it controls autocrine and paracrine pathways. While the majority of data imply rather beneficial roles of STAT3 in the heart, newer studies implicate that this is mainly the case when the expression and activation of STAT3 is precisely regulated. In contrast, continuous uncontrolled activation of STAT3 in cardiomyocytes seems to promote adverse cardiac remodeling processes especially after MI. Here, we provide an overview on STAT3 signaling and summarize the current understanding of the role of STAT3 for cardiac inflammation, metabolism, remodeling, and regeneration based on experimental and clinical studies. Finally, we highlight the consequences of targeting STAT3 for future therapeutic approaches in the setting of cardiac remodeling.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ADMA:

Asymmetric dimethylarginine

Bcl-3:

B cell lymphoma 3

CCL2:

Chemokine ligand 2

CCR2:

Chemokine ligand receptor 2

CLC:

Cardiotrophin-like cytokine

CNTF:

Ciliary neurotrophic factor

CT-1:

Cardiotrophin 1

CTGF:

Connective tissue growth factor

CVF:

Cobra venom factor

ECM:

Extracellular matrix

eNOS:

Endothelial nitric oxide synthase

EPO:

Erythropoietin

ERK:

Extracellular signal-regulated kinase

ETC:

Electron transport chain

G-CSF:

Granulocyte colony-stimulating factor

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

gp130:

Glycoprotein-130

HK2:

Hexokinase 2

IL:

Interleukin

JAK:

Janus kinase

LIF:

Leukemia inhibitory factor

LPS:

Lipopolysaccharide

LV:

Left ventricle

MBL:

Mannose-binding lectin

MHC:

Myosin heavy chain

MI:

Myocardial infarction

MMP:

Matrix metalloproteinase

OSM:

Oncostatin M

miRNA:

microRNA

NF-κB:

Nuclear factor-κB

PAI-1:

Plasminogen activator-1

PFKFB3:

6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3

PKB:

Protein kinase B, also known as AKT

PPAR:

Peroxisome proliferator-activated receptor

PPCM:

Peripartum cardiomyopathy

PIAS:

Protein inhibitors of activated STAT

PTPRT:

Protein tyrosine phosphatase receptor T

ROS:

Reactive oxygen species

SH2:

Src homology 2 domain

SHP2:

SH2 domain-containing cytoplasmatic protein

SOCS:

Suppressor of cytokine signaling

STAT3:

Signal transducer and activator of transcription 3

STAT3-KO:

STAT3-knockout

TAC:

Transverse aortic constriction

TIMP-1:

Tissue inhibitor of metalloproteinase-1

TNC:

Tenascin C

TNF-α:

Tumor necrosis factor-α

TSP-1:

Thrombospondin-1

Ube:

Ubiquitin-conjugating enzyme

UPS:

Ubiquitin–proteasome system

VEGF:

Vascular endothelial growth factor

References

  1. Forrester JS, Wyatt HL, Da Luz PL et al (1976) Functional significance of regional ischemic contraction abnormalities. Circulation 54:64–70

    Article  PubMed  CAS  Google Scholar 

  2. Dorn GW (2009) Novel pharmacotherapies to abrogate postinfarction ventricular remodeling. Nat Rev Cardiol 6:283–291

    Article  PubMed  CAS  Google Scholar 

  3. Boengler K, Hilfiker-Kleiner D, Drexler H et al (2008) The myocardial JAK/STAT pathway: from protection to failure. Pharmacol Ther 120:172–185

    Article  PubMed  CAS  Google Scholar 

  4. Fischer P, Hilfiker-Kleiner D (2007) Survival pathways in hypertrophy and heart failure: the gp130-STAT axis. Basic Res Cardiol 102:393–411

    Article  PubMed  CAS  Google Scholar 

  5. Haghikia A, Missol-Kolka E, Tsikas D et al (2011) Signal transducer and activator of transcription 3-mediated regulation of miR-199a-5p links cardiomyocyte and endothelial cell function in the heart: a key role for ubiquitin-conjugating enzymes. Eur Heart J 32:1287–1297

    Article  PubMed  CAS  Google Scholar 

  6. Haghikia A, Stapel B, Hoch M, Hilfiker-Kleiner D (2011) STAT3 and cardiac remodeling. Heart Fail Rev 16:35–47

    Article  PubMed  CAS  Google Scholar 

  7. Hilfiker-Kleiner D, Hilfiker A, Fuchs M et al (2004) Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ Res 95:187–195

    Article  PubMed  CAS  Google Scholar 

  8. Hilfiker-Kleiner D, Hilfiker A, Drexler H (2005) Many good reasons to have STAT3 in the heart. Pharmacol Ther 107:131–137

    Article  PubMed  CAS  Google Scholar 

  9. Hilfiker-Kleiner D, Kaminski K, Podewski E et al (2007) A Cathepsin D-Cleaved 16 kDa Form of Prolactin Mediates Postpartum Cardiomyopathy. Cell 128:589–600

    Article  PubMed  CAS  Google Scholar 

  10. Hilfiker-Kleiner D, Shukla P, Klein G et al (2010) Continuous glycoprotein-130-mediated signal transducer and activator of transcription-3 activation promotes inflammation, left ventricular rupture, and adverse outcome in subacute myocardial infarction. Circulation 122:145–155

    Article  PubMed  CAS  Google Scholar 

  11. Jacoby JJ, Kalinowski A, Liu MG et al (2003) Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. Proc Natl Acad Sci USA 100:12929–12934

    Article  PubMed  CAS  Google Scholar 

  12. Wegrzyn J, Potla R, Chwae YJ et al (2009) Function of mitochondrial Stat3 in cellular respiration. Science 323:793–797

    Article  PubMed  CAS  Google Scholar 

  13. Luedde M, Spaich S, Hippe HJ et al (2011) Affixin (beta-parvin) promotes cardioprotective signaling via STAT3 activation. J Mol Cell Cardiol 50:919–923

    Article  PubMed  CAS  Google Scholar 

  14. Kurdi M, Booz GW (2009) JAK redux: a second look at the regulation and role of JAKs in the heart. Am J Physiol Heart Circ Physiol 297:H1545–1556

    Article  PubMed  CAS  Google Scholar 

  15. Betz UA, Bloch W, van den Broek M et al (1998) Postnatally induced inactivation of gp130 in mice results in neurological, cardiac, hematopoietic, immunological, hepatic, and pulmonary defects. J Exp Med 188:1955–1965

    Article  PubMed  CAS  Google Scholar 

  16. Keller ET, Wanagat J, Ershler WB (1996) Molecular and cellular biology of interleukin-6 and its receptor. Front Biosci 1:d340–357

    PubMed  CAS  Google Scholar 

  17. Heinrich PC, Behrmann I, Muller-Newen G et al (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334:297–314

    PubMed  CAS  Google Scholar 

  18. Heinrich PC, Behrmann I, Haan S et al (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374:1–20

    Article  PubMed  CAS  Google Scholar 

  19. Olivier C, Auguste P, Chabbert M et al (2000) Identification of a gp130 cytokine receptor critical site involved in oncostatin M response. J Biol Chem 275:5648–5656

    Article  PubMed  CAS  Google Scholar 

  20. Pennica D, Wood WI, Chien KR (1996) Cardiotrophin-1: a multifunctional cytokine that signals via LIF receptor-gp 130 dependent pathways. Cytokine Growth Factor Rev 7:81–91

    Article  PubMed  CAS  Google Scholar 

  21. Plun-Favreau H, Perret D, Diveu C et al (2003) Leukemia inhibitory factor (LIF), cardiotrophin-1, and oncostatin M share structural binding determinants in the immunoglobulin-like domain of LIF receptor. J Biol Chem 278:27169–27179

    Article  PubMed  CAS  Google Scholar 

  22. Funamoto M, Hishinuma S, Fujio Y et al (2000) Isolation and characterization of the murine cardiotrophin-1 gene: expression and norepinephrine-induced transcriptional activation. J Mol Cell Cardiol 32:1275–1284

    Article  PubMed  CAS  Google Scholar 

  23. Hirano T, Nakajima K, Hibi M (1997) Signaling mechanisms through gp130: a model of the cytokine system. Cytokine Growth Factor Rev 8:241–252

    Article  PubMed  CAS  Google Scholar 

  24. Hirota H, Chen J, Betz UA et al (1999) Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell 97:189–198

    Article  PubMed  CAS  Google Scholar 

  25. Kunisada K, Hirota H, Fujio Y et al (1996) Activation of JAK-STAT and MAP kinases by leukemia inhibitory factor through gp130 in cardiac myocytes. Circulation 94:2626–2632

    Article  PubMed  CAS  Google Scholar 

  26. Oh H, Fujio Y, Kunisada K et al (1998) Activation of phosphatidylinositol 3-kinase through glycoprotein 130 induces protein kinase B and p70 S6 kinase phosphorylation in cardiac myocytes. J Biol Chem 273:9703–9710

    Article  PubMed  CAS  Google Scholar 

  27. Kishimoto T (1994) Signal transduction through homo- or heterodimers of gp130. Stem Cells 12(Suppl 1):37–44, discussion 44–35

    PubMed  Google Scholar 

  28. Murakami M, Hibi M, Nakagawa N et al (1993) IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Science 260:1808–1810

    Article  PubMed  CAS  Google Scholar 

  29. Abe K, Hirai M, Mizuno K et al (2001) The YXXQ motif in gp 130 is crucial for STAT3 phosphorylation at Ser727 through an H7-sensitive kinase pathway. Oncogene 20:3464–3474

    Article  PubMed  CAS  Google Scholar 

  30. Chen X, Vinkemeier U, Zhao Y et al (1998) Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell 93:827–839

    Article  PubMed  CAS  Google Scholar 

  31. Haspel RL, Salditt-Georgieff M, Darnell JE Jr (1996) The rapid inactivation of nuclear tyrosine phosphorylated Stat1 depends upon a protein tyrosine phosphatase. EMBO J 15:6262–6268

    PubMed  CAS  Google Scholar 

  32. Heinrich PC, Bode J, Decker M et al (2001) Termination and modulation of IL-6-type cytokine signaling. Adv Exp Med Biol 495:153–160

    Article  PubMed  CAS  Google Scholar 

  33. David M, Chen HE, Goelz S et al (1995) Differential regulation of the alpha/beta interferon-stimulated Jak/Stat pathway by the SH2 domain-containing tyrosine phosphatase SHPTP1. Mol Cell Biol 15:7050–7058

    PubMed  CAS  Google Scholar 

  34. Fischer P, Lehmann U, Sobota RM et al (2004) The role of the inhibitors of interleukin-6 signal transduction SHP2 and SOCS3 for desensitization of interleukin-6 signalling. Biochem J 378:449–460

    Article  PubMed  CAS  Google Scholar 

  35. Starr R, Hilton DJ (1999) Negative regulation of the JAK/STAT pathway. Bioessays 21:47–52

    Article  PubMed  CAS  Google Scholar 

  36. Lehmann U, Schmitz J, Weissenbach M et al (2003) SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130. J Biol Chem 278:661–671

    Article  PubMed  CAS  Google Scholar 

  37. Yasukawa H, Misawa H, Sakamoto H et al (1999) The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J 18:1309–1320

    Article  PubMed  CAS  Google Scholar 

  38. Yasukawa H, Hoshijima M, Gu Y et al (2001) Suppressor of cytokine signaling-3 is a biomechanical stress-inducible gene that suppresses gp130-mediated cardiac myocyte hypertrophy and survival pathways. J Clin Invest 108:1459–1467

    PubMed  CAS  Google Scholar 

  39. Zhang X, Guo A, Yu J et al (2007) Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T. Proc Natl Acad Sci USA 104:4060–4064

    Article  PubMed  CAS  Google Scholar 

  40. Ernst M, Jenkins BJ (2004) Acquiring signalling specificity from the cytokine receptor gp130. Trends Genet 20:23–32

    Article  PubMed  CAS  Google Scholar 

  41. Fischer P, Hilfiker-Kleiner D (2008) Role of gp130-mediated signalling pathways in the heart and its impact on potential therapeutic aspects. Br J Pharmacol 153(Suppl 1):414–427

    Google Scholar 

  42. Tebbutt NC, Giraud AS, Inglese M et al (2002) Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med 8:1089–1097

    Article  PubMed  CAS  Google Scholar 

  43. Yamauchi-Takihara K, Hirota H, Kunisada K et al (1996) Roles of gp130 signaling pathways in cardiac myocytes: recent advances and implications for cardiovascular disease. J Card Fail 2(4 Suppl):S63–68

    Article  PubMed  CAS  Google Scholar 

  44. Yamauchi-Takihara K (2002) Gp130-mediated pathway and left ventricular remodeling. J Card Fail 8(6 Suppl):S374–378

    Article  PubMed  CAS  Google Scholar 

  45. Akira S, Nishio Y, Inoue M et al (1994) Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77:63–71

    Article  PubMed  CAS  Google Scholar 

  46. Zhong Z, Wen Z, Darnell JE Jr (1994) Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264:95–98

    Article  PubMed  CAS  Google Scholar 

  47. Aggarwal BB, Kunnumakkara AB, Harikumar KB et al (2009) Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann N Y Acad Sci 1171:59–76

    Article  PubMed  CAS  Google Scholar 

  48. Zhang Z, Fuller GM (1997) The competitive binding of STAT3 and NF-kappa B on an overlapping DNA binding site. Biochem Biophys Res Commun 237:90–94

    Article  PubMed  Google Scholar 

  49. Zhang H, Wang HY, Bassel-Duby R et al (2007) Role of interleukin-6 in cardiac inflammation and dysfunction after burn complicated by sepsis. Am J Physiol Heart Circ Physiol 292:H2408–2416

    Article  PubMed  CAS  Google Scholar 

  50. Krishnamurthy P, Rajasingh J, Lambers E et al (2009) IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR. Circ Res 104:e9–18

    Article  PubMed  CAS  Google Scholar 

  51. Dewald O, Ren G, Duerr GD et al (2004) Of mice and dogs: species-specific differences in the inflammatory response following myocardial infarction. Am J Pathol 164:665–677

    Article  PubMed  CAS  Google Scholar 

  52. Frangogiannis NG, Mendoza LH, Lindsey ML et al (2000) IL-10 is induced in the reperfused myocardium and may modulate the reaction to injury. J Immunol 165:2798–2808

    PubMed  CAS  Google Scholar 

  53. Murray PJ (2006) STAT3-mediated anti-inflammatory signalling. Biochem Soc Trans 34:1028–1031

    Article  PubMed  CAS  Google Scholar 

  54. Williams LM, Sarma U, Willets K et al (2007) Expression of constitutively active STAT3 can replicate the cytokine-suppressive activity of interleukin-10 in human primary macrophages. J Biol Chem 282:6965–6975

    Article  PubMed  CAS  Google Scholar 

  55. Daftarian PM, Kumar A, Kryworuchko M, Diaz-Mitoma F (1996) IL-10 production is enhanced in human T cells by IL-12 and IL-6 and in monocytes by tumor necrosis factor-alpha. J Immunol 157:12–20

    PubMed  CAS  Google Scholar 

  56. Yajima T, Murofushi Y, Zhou H et al (2011) Absence of SOCS3 in the cardiomyocyte increases mortality in a gp130-dependent manner accompanied by contractile dysfunction and ventricular arrhythmias. Circulation 124:2690–2701

    Article  PubMed  Google Scholar 

  57. Manukyan MC, Alvernaz CH, Poynter JA et al (2011) Interleukin-10 protects the ischemic heart from reperfusion injury via the STAT3 pathway. Surgery 150:231–239

    Article  PubMed  Google Scholar 

  58. Obana M, Maeda M, Takeda K et al (2010) Therapeutic activation of signal transducer and activator of transcription 3 by interleukin-11 ameliorates cardiac fibrosis after myocardial infarction. Circulation 121:684–691

    Article  PubMed  CAS  Google Scholar 

  59. Deten A, Volz HC, Briest W, Zimmer HG (2003) Differential cytokine expression in myocytes and non-myocytes after myocardial infarction in rats. Mol Cell Biochem 242:47–55

    Article  PubMed  CAS  Google Scholar 

  60. Yue P, Massie BM, Simpson PC, Long CS (1998) Cytokine expression increases in nonmyocytes from rats with postinfarction heart failure. Am J Physiol 275:H250–258

    PubMed  CAS  Google Scholar 

  61. Yajima T, Yasukawa H, Jeon ES et al (2006) Innate defense mechanism against virus infection within the cardiac myocyte requiring gp130-STAT3 signaling. Circulation 114:2364–2373

    Article  PubMed  CAS  Google Scholar 

  62. Valdembri D, Serini G, Vacca A et al (2002) In vivo activation of JAK2/STAT-3 pathway during angiogenesis induced by GM-CSF. FASEB J 16:225–227

    PubMed  CAS  Google Scholar 

  63. Kano A, Wolfgang MJ, Gao Q et al (2003) Endothelial cells require STAT3 for protection against endotoxin-induced inflammation. J Exp Med 198:1517–1525

    Article  PubMed  CAS  Google Scholar 

  64. Osugi T, Oshima Y, Fujio Y et al (2002) Cardiac-specific Activation of Signal Transducer and Activator of Transcription 3 Promotes Vascular Formation in the Heart. J Biol Chem 277:6676–6681

    Article  PubMed  CAS  Google Scholar 

  65. Dor Y, Djonov V, Abramovitch R et al (2002) Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J 21:1939–1947

    Article  PubMed  CAS  Google Scholar 

  66. Funamoto M, Fujio Y, Kunisada K et al (2000) Signal transducer and activator of transcription 3 is required for glycoprotein 130-mediated induction of vascular endothelial growth factor in cardiac myocytes. J Biol Chem 275:10561–10566

    Article  PubMed  CAS  Google Scholar 

  67. Kunisada K, Negoro S, Tone E et al (2000) Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy. Proc Natl Acad Sci USA 97:315–319

    Article  PubMed  CAS  Google Scholar 

  68. Inoki I, Shiomi T, Hashimoto G et al (2002) Connective tissue growth factor binds vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis. FASEB J 16:219–221

    PubMed  CAS  Google Scholar 

  69. Rodriguez-Manzaneque JC, Lane TF, Ortega MA et al (2001) Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci USA 98:12485–12490

    Article  PubMed  CAS  Google Scholar 

  70. Bloomston M, Shafii A, Zervos EE, Rosemurgy AS (2002) TIMP-1 overexpression in pancreatic cancer attenuates tumor growth, decreases implantation and metastasis, and inhibits angiogenesis. J Surg Res 102:39–44

    Article  PubMed  CAS  Google Scholar 

  71. Volpert OV, Zaichuk T, Zhou W et al (2002) Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor. Nat Med 8:349–357

    Article  PubMed  CAS  Google Scholar 

  72. Ahmed MS, Oie E, Vinge LE et al (2004) Connective tissue growth factor–a novel mediator of angiotensin II-stimulated cardiac fibroblast activation in heart failure in rats. J Mol Cell Cardiol 36:393–404

    Article  PubMed  CAS  Google Scholar 

  73. Edelberg JM, Reed MJ (2003) Aging and angiogenesis. Front Biosci 8:s1199–1209

    Article  PubMed  CAS  Google Scholar 

  74. Ingber DE (2002) Mechanical signaling and the cellular response to extracellular matrix in angiogenesis and cardiovascular physiology. Circ Res 91:877–887

    Article  PubMed  CAS  Google Scholar 

  75. Fukuda S, Kaga S, Sasaki H et al (2004) Angiogenic signal triggered by ischemic stress induces myocardial repair in rat during chronic infarction. J Mol Cell Cardiol 36:547–559

    Article  PubMed  CAS  Google Scholar 

  76. Harada M, Qin Y, Takano H et al (2005) G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nat Med 11:305–311

    Article  PubMed  CAS  Google Scholar 

  77. Mohri T, Fujio Y, Maeda M et al (2006) Leukemia inhibitory factor induces endothelial differentiation in cardiac stem cells. J Biol Chem 281:6442–6447

    Article  PubMed  CAS  Google Scholar 

  78. Mohri T, Fujio Y, Obana M et al (2009) Signals through glycoprotein 130 regulate the endothelial differentiation of cardiac stem cells. Arterioscler Thromb Vasc Biol 29:754–760

    Article  PubMed  CAS  Google Scholar 

  79. Hoch M, Fischer P, Stapel B et al (2011) Erythropoietin preserves the endothelial differentiation capacity of cardiac progenitor cells and reduces heart failure during anticancer therapies. Cell Stem Cell 9:131–143

    Article  PubMed  CAS  Google Scholar 

  80. van Bilsen M, van Nieuwenhoven FA, van der Vusse GJ (2009) Metabolic remodelling of the failing heart: beneficial or detrimental? Cardiovasc Res 81:420–428

    Article  PubMed  Google Scholar 

  81. Demaria M, Giorgi C, Lebiedzinska M et al (2010) A STAT3-mediated metabolic switch is involved in tumour transformation and STAT3 addiction. Aging (Albany NY) 2:823–842

    CAS  Google Scholar 

  82. Ando M, Uehara I, Kogure K et al (2010) Interleukin 6 enhances glycolysis through expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3. J Nihon Med Sch 77:97–105

    Article  CAS  Google Scholar 

  83. Jiang S, Zhang LF, Zhang HW et al (2012) A novel miR-155/miR-143 cascade controls glycolysis by regulating hexokinase 2 in breast cancer cells. EMBO J 31:1985–1998

    Article  PubMed  CAS  Google Scholar 

  84. Inoue H, Ogawa W, Ozaki M et al (2004) Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. Nat Med 10:168–174

    Article  PubMed  CAS  Google Scholar 

  85. Park SY, Cho YR, Finck BN et al (2005) Cardiac-specific overexpression of peroxisome proliferator-activated receptor-alpha causes insulin resistance in heart and liver. Diabetes 54:2514–2524

    Article  PubMed  CAS  Google Scholar 

  86. Akasaka Y, Tsunoda M, Ogata T et al (2010) Direct evidence for leptin-induced lipid oxidation independent of long-form leptin receptor. Biochim Biophys Acta 1801:1115–1122

    Article  PubMed  CAS  Google Scholar 

  87. Neubauer S (2007) The failing heart–an engine out of fuel. N Engl J Med 356:1140–1151

    Article  PubMed  Google Scholar 

  88. Boengler K, Hilfiker-Kleiner D, Heusch G, Schulz R (2010) Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion. Basic Res Cardiol 105:771–785

    Article  PubMed  CAS  Google Scholar 

  89. Szczepanek K, Chen Q, Derecka M et al (2011) Mitochondrial-targeted Signal transducer and activator of transcription 3 (STAT3) protects against ischemia-induced changes in the electron transport chain and the generation of reactive oxygen species. J Biol Chem 286:29610–29620

    Article  PubMed  CAS  Google Scholar 

  90. Phillips D, Reilley MJ, Aponte AM et al (2010) Stoichiometry of STAT3 and mitochondrial proteins: Implications for the regulation of oxidative phosphorylation by protein-protein interactions. J Biol Chem 285:23532–23536

    Article  PubMed  CAS  Google Scholar 

  91. Beckles DL, Mascareno E, Siddiqui MA (2006) Inhibition of Jak2 phosphorylation attenuates pressure overload cardiac hypertrophy. Vascul Pharmacol 45:350–357

    Article  PubMed  CAS  Google Scholar 

  92. Podewski EK, Hilfiker-Kleiner D, Hilfiker A et al (2003) Alterations in Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling in patients with end-stage dilated cardiomyopathy. Circulation 107:798–802

    Article  PubMed  CAS  Google Scholar 

  93. Negoro S, Kunisada K, Fujio Y et al (2001) Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutase. Circulation 104:979–981

    Article  PubMed  CAS  Google Scholar 

  94. Rattazzi M, Puato M, Faggin E et al (2003) C-reactive protein and interleukin-6 in vascular disease: culprits or passive bystanders? J Hypertens 21:1787–1803

    Article  PubMed  CAS  Google Scholar 

  95. Tsutamoto T, Hisanaga T, Wada A et al (1998) Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol 31:391–398

    Article  PubMed  CAS  Google Scholar 

  96. Ohtsuka T, Hamada M, Inoue K et al (2004) Relation of circulating interleukin-6 to left ventricular remodeling in patients with reperfused anterior myocardial infarction. Clin Cardiol 27:417–420

    Article  PubMed  Google Scholar 

  97. Heimberger AB, Priebe W (2008) Small molecular inhibitors of p-STAT3: novel agents for treatment of primary and metastatic CNS cancers. Recent Patents CNS Drug Discov 3:179–188

    Article  CAS  Google Scholar 

Download references

Acknowledgment

We thank the DFG for supporting this work.

Author information

Authors and Affiliations

  1. Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany

    Melanie Ricke-Hoch, Britta Stapel, Irina Gorst, Arash Haghikia & Denise Hilfiker-Kleiner

Authors
  1. Melanie Ricke-Hoch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Britta Stapel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Irina Gorst
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arash Haghikia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Denise Hilfiker-Kleiner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Melanie Ricke-Hoch .

Editor information

Editors and Affiliations

  1. Walter MacKenzie Health Sciences Centre, Division of Cardiology, University of Alberta, 8440-112 Street, Edmonton, T6G 2B7, Alberta, Canada

    Bodh I. Jugdutt

  2. St. Boniface General Hospital Research C, Institute of Cardiovascular Sciences, Tache Avenue 351, Winnipeg, R2H 2A6, Manitoba, Canada

    Naranjan S. Dhalla

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Ricke-Hoch, M., Stapel, B., Gorst, I., Haghikia, A., Hilfiker-Kleiner, D. (2013). The STAT3 Pathway and Downstream Mechanisms in Cardiac Remodeling: Friend or Foe. In: Jugdutt, B., Dhalla, N. (eds) Cardiac Remodeling. Advances in Biochemistry in Health and Disease, vol 5. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5930-9_20

Download citation

Publish with us

Policies and ethics

Search

Navigation