Cardiac-specific Activation of Signal Transducer and Activator of Transcription 3 Promotes Vascular Formation in the Heart

Osugi, Tomoaki; Oshima, Yoshifumi; Fujio, Yasushi; Funamoto, Masanobu; Yamashita, Atsuko; Negoro, Shinji; Kunisada, Keita; Izumi, Mitsuru; Nakaoka, Yoshikazu; Hirota, Hisao; Okabe, Masaru; Yamauchi–Takihara, Keiko; Kawase, Ichiro; Kishimoto, Tadamitsu

doi:10.1074/jbc.m108246200

Cited by 141 publications

(110 citation statements)

References 38 publications

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“…A commercially available human angiogenesis kit, used for the assessment of angiogenesis in vitro (Bishop et al, 2000;Donovan et al, 2001;Terai et al, 2001;Drinkwater et al, 2002;Osugi et al, 2002) was provided by TCS Cellworks. The assay is supplied as growing cultures of HUVECs at the earliest stages of tubule formation in a 24 well plate format.…”

Section: Human Angiogenesis Kitmentioning

confidence: 99%

Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects

et al. 2002

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The anti-tumour effects of thalidomide have been associated with its anti-angiogenic properties. Second generation thalidomide analogues are distinct compounds with enhanced therapeutic potential. Although these compounds are beginning to enter trials for the treatment of cancer there is very little information regarding the anti-angiogenic activity of these clinically relevant compounds. Furthermore, it is not known how the various immunomodulatory activities of these compounds relate to anti-angiogenic activity. In this study we assessed the anti-angiogenic activity of compounds from both IMiD TM and SelCID TM classes of analogues using a novel in vitro multicellular human assay system and the established rat aorta assay. Our results show that both the IMiDs and SelCIDs tested are significantly more potent than thalidomide. The anti-angiogenic potency of the analogues was not related to inhibition of endothelial cell proliferation, nor their TNF-a/PDE type 4 inhibitory properties. However, anti-migratory effects in vitro and inhibition of tumour growth in vivo was observed with the analogue IMiD-1 (clinically known as REVIMID TM ). Our results show that anti-angiogenic activity spans both currently defined classes of thalidomide analogue and is not related to their previously described immunomodulatory properties. Identification of the differential effects of these compounds will enable targeting of such compounds into the appropriate clinical setting.

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Section: Human Angiogenesis Kitmentioning

confidence: 99%

Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects

et al. 2002

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“…Recently, STAT3 was shown to induce tumor angiogenesis through upregulation of VEGF expression (Niu et al, 2002). Transgenic mice overexpressing constitutively activated STAT3C display enhanced heart vascularization (Osugi et al, 2001). Constitutive activation of STATs 1-3 is detected in lymph nodes infiltrated by breast tumor cells (Bowman et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Disruption of STAT3 signaling leads to tumor cell invasion through alterations of homotypic cell–cell adhesion complexes

et al. 2004

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STAT3 is frequently overexpressed and constitutively activated by tyrosine phosphorylation during malignant transformation. Despite the clear importance of STAT3 in cell proliferation and survival in diverse human cancers, its possible contribution to tumor cell adhesion, motility and invasion remains hypothetical. We therefore compared the transforming properties of STAT3wt, its constitutively activated dimeric form STAT3C, and the dominant negative mutant STAT3-Y705F in human colorectal HCT8/S11 cancer cells. Both STAT3wt and STAT3C exert a permissive action to the proinvasive activity of the scatter factor HGF in HCT8/S11 cells. In contrast, the monomeric and cytoplasmic mutant Y705F induces a constitutive invasive phenotype through Wnt/Rho-independent and EGFR/PI3-kinase-dependent pathways. Accordingly, Y705F decreases cell-cell homotypic adhesions, and increases cell motility and scattering, as well as lamellipodia-type cellular extensions. STAT3-Y705F-transfected HCT8/S11 cells display an increased tyrosine phosphorylation of the cell-cell adhesion regulator bcatenin and its dissociation from the invasion suppressor E-cadherin at cell-cell contacts. Our data imply that both invasion promoter and repressor genes are controlled by the canonical STAT3 transcription pathways. Disruption of this cascade by Y705F reveals the proinvasive potential of altered forms of STAT3 as a persistent signaling adaptor in cytokine/transforming growth factor receptor scaffolds and oncogenic pathways.

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“…Each of these gp130 downstream signaling pathways has been demonstrated to play an important role in cardiac physiology. Particularly STAT3-dependent downstream signaling of gp130 holds a key role in cardiac hypertrophy and protective effects during its maladaptive transition to heart failure such as cardiac angiogenesis and prevention of cardiomyocyte apoptosis [51,64,78,107].…”

Section: Introductionmentioning

confidence: 99%

Survival pathways in hypertrophy and heart failure: The gp130-STAT3 axis

2007

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■ Abstract Circulating levels of interleukin (IL)-6 and related cytokines are elevated in patients with congestive heart failure and after myocardial infarction. Serum IL-6 concentrations are related to decreasing functional status of these patients and provide important prognostic information. Moreover, in the failing human heart, multiple components of the IL-6-glycoprotein (gp)130 receptor system are impaired, implicating an important role of this system in cardiac pathophysiology.Experimental studies have shown that the common receptor subunit of IL-6 cytokines is phosphorylated in response to pressure overload and myocardial infarction and that it subsequently activates at least three different downstream signaling pathways, the signal transducers and activators of transcription 1 and 3 (STAT1/3), the Src-homology tyrosine phosphatase 2 (SHP2)-Ras-ERK, and the PI3K-Akt system. Gp130 receptor mediated signaling promotes cardiomyocyte survival, induces hypertrophy, modulates cardiac extracellular matrix and cardiac function. In this regard, the gp130 receptor system and its main downstream mediator STAT3 play a key role in cardioprotection.This review summarizes the current knowledge of IL-6 cytokines, gp130 receptor and STAT3 signaling in the heart exposed to physiological (aging, pregnancy) and pathophysiological stress (ischemia, pressure overload, inflammation and cardiotoxic agents) with a special focus on the potential role of individual IL-6 cytokines.

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Cardiac-specific Activation of Signal Transducer and Activator of Transcription 3 Promotes Vascular Formation in the Heart

Cited by 141 publications

References 38 publications

Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects

Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects

Disruption of STAT3 signaling leads to tumor cell invasion through alterations of homotypic cell–cell adhesion complexes

Survival pathways in hypertrophy and heart failure: The gp130-STAT3 axis

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