Heparin-Binding Epidermal Growth Factor-Like Growth Factor Protects Rat Intestine from Ischemia/Reperfusion Injury

Pillai, Srikumar; Hinman, Christina E.; Luquette, Mark; Nowicki, Philip T.; Besner, Gail E.

doi:10.1006/jsre.1999.5764

Cited by 56 publications

(38 citation statements)

References 46 publications

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“…In the case of puromycin aminonucleoside nephrosis (15), increased glomerular HB-EGF expression may explain, in part, the increased glomerular HK activity reported by Dubach and Recant in this model over forty years ago (1). Although the functional significance of these changes have not been defined and pathogenetic contributions cannot presently be excluded, recent demonstrations of reparative and cytoprotective effects of HB-EGF and other EGFR ligands in both renal (55,56) and other tissue (57,58) injury models suggest that these growth factors, and HB-EGF in particular, may also play an important role in the response to, rather than the mediation of, acute glomerular injury (59).…”

Section: Figmentioning

confidence: 82%

Regulation of Mesangial Cell Hexokinase Activity and Expression by Heparin-binding Epidermal Growth Factor-like Growth Factor

Robey¹,

Ma²,

Santos³

et al. 2002

Journal of Biological Chemistry

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Heparin-binding epidermal growth factor -like growth factor (HB-EGF) expression and hexokinase (HK) activity are increased in various pathologic renal conditions. Although the mitogenic properties of HB-EGF have been well characterized, its effects on glucose (Glc) metabolism have not. We therefore examined the possibility that HB-EGF might regulate HK activity and expression in glomerular mesangial cells, which constitute the principal renal cell type affected by a variety of pathologic conditions. Protein kinase C (PKC)-dependent classic mitogenactivated protein kinase (MAPK) pathway activation has been associated with increased HK activity in this cell type, so we also examined dependence upon these signaling intermediates. HB-EGF (>10 nM) increased total HK activity over 50% within 12-24 h, an effect mimicked by other EGF receptor agonists, but not by IGF-1 or elevated Glc. EGF receptor and classic MAPK pathway antagonists prevented this increase, as did general inhibitors of gene transcription and protein synthesis. Both HB-EGF and phorbol esters activated the classic MAPK pathway, albeit via PKC-independent and PKC-dependent mechanisms, respectively. Both stimuli were associated with increased HK activity, selectively increased HKII isoform expression, and increased Glc metabolism via both the glycolytic-tricarboxylic acid cycle route and the pentose phosphate pathway. HB-EGF thus constitutes a novel regulator of mesangial cell HK activity and Glc metabolism. HKII is the principal regulated isoform in these cells, as it is in insulin-sensitive peripheral tissues, such as muscle. However, the uniform requirement for classic MAPK pathway activation distinguishes HKII regulation in mesangial cells from that observed in muscle. These findings suggest a novel mechanism whereby growth factors may couple metabolism to glomerular injury.

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Section: Figmentioning

confidence: 82%

Regulation of Mesangial Cell Hexokinase Activity and Expression by Heparin-binding Epidermal Growth Factor-like Growth Factor

Robey¹,

Ma²,

Santos³

et al. 2002

Journal of Biological Chemistry

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“…Indeed, a specific inhibitor of iNOS given orally provided protection in a model of IBD (35). We have shown that administration of HB-EGF protects rat intestine from I/R injury; decreases post-I/R iNOS expression, NO production, and reactive oxygen species production; and decreases neutrophil infiltration and bacterial translocation (22,23). We have not examined the effects of HB-EGF on endothelial NOS or neuronal NOS, but from the data presented in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…We have shown that HB-EGF decreases iNOS expression and NO production in a colon carcinoma cell line (21) and in a rat model of ischemia/ reperfusion (I/R) injury (22). HB-EGF also protected rat intestine from histologic damage (23), decreased reactive oxygen species production in polymorphonuclear leukocytes (24), and protected DLD-1 cells from proinflammatory cytokine-induced apoptosis (25). However, the molecular mechanisms of HB-EGF action have not yet been elucidated.…”

Section: Inhibition Of Nf-b Activation and Its Target Genes By Heparimentioning

confidence: 99%

Inhibition of NF-κB Activation and Its Target Genes by Heparin-Binding Epidermal Growth Factor-Like Growth Factor

Mehta¹,

Besner²

2003

The Journal of Immunology

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Many cells upon injury mount extensive, compensatory responses that increase cell survival; however, the intracellular signals that regulate these responses are not completely understood. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been implicated as a cytoprotective agent. We have previously demonstrated that pretreatment of human intestinal epithelial cells with HB-EGF significantly decreased cytokine-induced activation of inducible NO synthase mRNA expression and NO production and protected the cells from apoptosis and necrosis. However, the mechanisms by which HB-EGF exerts these effects are not known. Here we show that cytokine exposure (IL-1β and IFN-γ) induced NF-κB activation and IL-8 and NO production in DLD-1 cells. Transient expression of a dominant negative form of IκBα decreased NO production, suggesting that the cytokines stimulated NO production in part through activation of NF-κB. HB-EGF dramatically suppressed NF-κB activity and IL-8 release and decreased NO production in cells pretreated with HB-EGF. HB-EGF blocked NF-κB activation by inhibiting IκB kinase activation and IκB phosphorylation and degradation, thus interfering with NF-κB nuclear translocation, DNA-binding activity, and NF-κB-dependent transcriptional activity. The data demonstrate that HB-EGF decreases inflammatory cytokine and NO production by interfering with the NF-κB signaling pathway. Inhibition of NF-κB may represent one of the mechanisms by which HB-EGF exerts its potent anti-inflammatory and cytoprotective effects.

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“…9,10 In contrast, HB-EGF is therapeutic for the skin, 11,12 kidney, 13,14 liver, and small intestine. 3,5,15,16 HB-EGF is markedly upregulated during the acute phase of injury and plays an essential role in epithelial cell repair, proliferation and regeneration in these organs. 5,11,13,15,17 Further direct evidence of therapeutic benefit was provided by studies of administration of recombinant HB-EGF in animal ischemic disease models.…”

mentioning

confidence: 99%

“…5,11,13,15,17 Further direct evidence of therapeutic benefit was provided by studies of administration of recombinant HB-EGF in animal ischemic disease models. 16 Thus, HB-EGF plays a number of physiological roles, and its effects are diverse and even opposing in nature depending on the tissues examined.…”

mentioning

confidence: 99%

Local overexpression of HB-EGF exacerbates remodeling following myocardial infarction by activating noncardiomyocytes

Ushikoshi

Takahashi

Chen

et al. 2005

Laboratory Investigation

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Insulin-like growth factor (IGF), hepatocyte growth factor (HGF), and heparin-binding epidermal growth factorlike growth factor (HB-EGF) are cardiogenic and cardiohypertrophic growth factors. Although the therapeutic effects of IGF and HGF have been well demonstrated in injured hearts, it is uncertain whether natural upregulation of HB-EGF after myocardial infarction (MI) plays a beneficial or pathological role in the process of remodeling. To answer this question, we conducted adenoviral HB-EGF gene transduction in in vitro and in vivo injured heart models, allowing us to highlight and explore the HB-EGF-induced phenotypes. Overexpressed HB-EGF had no cytoprotective or additive death-inducible effect on Fas-induced apoptosis or oxidative stress injury in primary cultured mouse cardiomyocytes, although it significantly induced hypertrophy of cardiomyocytes and proliferation of cardiac fibroblasts. Locally overexpressed HB-EGF in the MI border area in rabbit hearts did not improve cardiac function or exhibit an angiogenic effect, and instead exacerbated remodeling at the subacute and chronic stages post-MI. Namely, it elevated the levels of apoptosis, fibrosis, and the accumulation of myofibroblasts and macrophages in the MI area, in addition to inducing left ventricular hypertrophy. Thus, upregulated HB-EGF plays a pathophysiological role in injured hearts in contrast to the therapeutic roles of IGF and HGF. These results imply that regulation of HB-EGF may be a therapeutic target for treating cardiac hypertrophy and fibrosis. Laboratory Investigation (2005) 85, 862-873.

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Heparin-Binding Epidermal Growth Factor-Like Growth Factor Protects Rat Intestine from Ischemia/Reperfusion Injury

Cited by 56 publications

References 46 publications

Regulation of Mesangial Cell Hexokinase Activity and Expression by Heparin-binding Epidermal Growth Factor-like Growth Factor

Regulation of Mesangial Cell Hexokinase Activity and Expression by Heparin-binding Epidermal Growth Factor-like Growth Factor

Inhibition of NF-κB Activation and Its Target Genes by Heparin-Binding Epidermal Growth Factor-Like Growth Factor

Local overexpression of HB-EGF exacerbates remodeling following myocardial infarction by activating noncardiomyocytes

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