Functional components of basic fibroblast growth factor signaling that inhibit lung elastin gene expression

Carreras, Isabel; Rich, Celeste B.; Jaworski, Julie; DiCamillo, Sandra J.; Panchenko, Mikhail P.; Goldstein, Ronald H.; Foster, Jeffrey S.

doi:10.1152/ajplung.2001.281.4.l766

Cited by 25 publications

(35 citation statements)

References 36 publications

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“…We first established that elastase treatment of matrix-laden pulmonary fibroblast cultures resulted in a detectable amount of soluble HB-EGF within the elastase-released products. Addition of soluble HB-EGF to undigested fibroblast cultures decreased the steady-state level of elastin mRNA through a mechanism similar to that reported for FGF-2 (6,42). Furthermore, we show that HB-EGF treatment of pulmonary fibroblasts leads to an increase in endogenous FGF-2 mRNA and protein levels.…”

supporting

confidence: 80%

Heparin-binding EGF-like growth factor regulates elastin and FGF-2 expression in pulmonary fibroblasts

Liu

Rich

Buczek‐Thomas

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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.-Elastase degradation of elastin within alveolar walls is an important event in the development of pulmonary emphysema. In addition to elastolytic activities, elastases release growth factors from extracellular matrices and interstitial cell surfaces that can regulate elastogenesis and other cellular responses. In the present study, we demonstrate that brief treatment of matrix-laden rat pulmonary fibroblast cultures with pancreatic elastase results in the release of soluble heparin-binding epidermal growth factorlike growth factor (HB-EGF) concomitant with a decrease in HB-EGF binding to both heparan sulfate proteoglycan and receptor sites on the cells. In undigested, matrix-laden fibroblasts, HB-EGF significantly downregulates elastin mRNA via activation of epidermal growth factor receptor. Results from nuclear run-on analyses show that HB-EGF downregulates elastin mRNA via transcriptional suppression. HB-EGF treatment stimulates MAP or ERK kinase (MEK)-dependent ERK1/2 phosphorylation and leads to nuclear accumulation of Fra-1. Blocking ERK1/2 activation by MEK1/2 inhibitors (PD-98059 or U-0126) diminishes HB-EGF-induced Fra-1 accumulation and subsequent downregulation of elastin mRNA. Coaddition of two elastase-released growth factors, HB-EGF and FGF-2, results in an additive inhibitory effect on elastin mRNA levels. Furthermore, HB-EGF addition to pulmonary fibroblasts increases FGF-2 mRNA and protein levels. These data suggest that HB-EGF and FGF-2 act in concert to regulate the synthesis of elastin in injury/ repair situations. elastin; heparin-binding epidermal growth factor-like growth factor; epidermal growth factor receptor; fibroblast growth factor-2; heparan sulfate proteoglycan; transcription; extracellular signal-regulated kinase 1/2; Fra-1 LUNG INTERSTITIAL ELASTIN plays a critical role in allowing air exchange through the alveolar network. This role is underlined in the development of chronic obstructive pulmonary disease (COPD) such as emphysema, where proteolytic degradation of elastin within alveolar walls is associated with the destruction of lung architecture and the concomitant loss of lung function.Elastin is synthesized as a soluble precursor, tropoelastin, that is secreted and cross-linked to form insoluble elastic fibers. In rodents, lung elastin gene expression is high during late fetal and early postnatal development, when the majority of elastin mRNA is localized in the pulmonary vasculature and later in the forming alveolar septa and crests (32). Elastin gene expression decreases afterwards, and there is very little elastin synthesis in adults. Temporal and spatial association of elastin synthesis with specific developmental events suggests that elastin plays an active role in lung morphogenesis. Indeed, elastin deposition within the tips of the secondary septa is thought to be a driving force for alveolarization in rodent postnatal lung development (3,8,27). In addition, elastin-deficient mice exhibit retarded lung branching morphology at birth, suggesting an earlier contribution...

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supporting

confidence: 80%

Heparin-binding EGF-like growth factor regulates elastin and FGF-2 expression in pulmonary fibroblasts

Liu

Rich

Buczek‐Thomas

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…6,14,15 Thus, inhibition of its phosphorylation seems to be a promising strategy to regulate elastin synthesis in models deficient in elastin content. Using aortic vSMCs isolated from the BN rat, an inbred strain deficient in elastin synthesis, we demonstrated that inhibition of ERK1/2 phosphorylation by U0126, an inhibitor of MEK1/2 activity, increases elastin gene transcription.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 The mechanism most studied is probably the decreased elastin gene transcription by bFGF in human vSMCs 10 and rat pulmonary fibroblasts. [11][12][13][14] EGF and bFGF were shown to decrease elastin gene transcription by activating extracellular signalregulated kinases 1/2 (ERK1/2), resulting in its translocation to the nucleus and subsequent induction of c-fos and fra1. 10,[13][14][15] Heterodimers c-fos/c-jun and fra1/c-jun form the activator protein-1 (AP1) complex that represses elastin gene transcription through its binding to an AP1/cAMP response element-like sequence located on the human elastin gene.…”

mentioning

confidence: 99%

“…[11][12][13][14] EGF and bFGF were shown to decrease elastin gene transcription by activating extracellular signalregulated kinases 1/2 (ERK1/2), resulting in its translocation to the nucleus and subsequent induction of c-fos and fra1. 10,[13][14][15] Heterodimers c-fos/c-jun and fra1/c-jun form the activator protein-1 (AP1) complex that represses elastin gene transcription through its binding to an AP1/cAMP response element-like sequence located on the human elastin gene. 5,10,13,16 However, these cytokines and growth factors have limitations for clinical use in patients with abnormal elastin metabolism.…”

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confidence: 99%

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Inhibition of ERK1/2 Phosphorylation: A New Strategy to Stimulate Elastogenesis in the Aorta

et al. 2014

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Abstract-Haploinsufficiency of elastin leads, in more than half of patients with Williams-Beuren syndrome, to development of supravalvular aortic stenosis and hypertension. Determining mechanisms implicated in elastin synthesis would be of interest to find new elastogenic molecules to treat such a pathology. Here, we analyzed the signaling pathway linking intracellular calcium concentration to elastin regulation to find new molecules able to increase elastin synthesis. Their elastogenic ability was then investigated, in vitro and in vivo, using inhibitors of the highlighted pathway. The Brown Norway rat strain was used here as an arterial elastin-deficient model. Our data indicated that A23187, a calcium ionophore, decreases elastin expression in cultured vascular smooth muscle cells, both transcriptionally and post-transcriptionally. Addition of A23187 induced transient activation of extracellular signal-regulated kinases 1/2, leading to an upregulation of activator protein-1 transcription factors, which correlated with the inhibition of elastin gene transcription. Pretreatment with U0126, an inhibitor of extracellular signal-regulated kinases 1/2 phosphorylation, abolished the inhibition of elastin gene transcription by A23187. In vitro, U0126 increased elastin synthesis and in vivo, 24 hours after an intravenous administration, elastin gene transcription and elastin mRNA levels were increased in the rat aorta. A chronic treatment, diffusing U0126 for 10 weeks, increased aortic elastin content without changing cell number and collagen content. In conclusion, calcium ionophore represses elastin gene transcription via activation of extracellular signal-regulated kinases 1/2 pathway and activator protein-1 transcription factors. Moreover, we provide strong evidence that inhibition of extracellular signal-regulated kinases 1/2 increases elastin synthesis and could thus be suitable for treating vascular pathologies characterized by diminished arterial elastin content. (Hypertension. 2014;64:423-430.) • Online Data Supplement

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“…Carreras et al demonstrated that bFGF-mediated activation of the MAPKElk-1 pathway plays a pivotal role in the transcriptional repression of the ECM component elastin in lung fibroblasts (Carreras et al, 2001). Similarly, in human articular chondrocytes, the stimulation of multiple MAPK pathways subsequently activates the downstream transcription factor Elk-1, which then translocates into the nucleus and stimulates MMP-13 gene expression through protein-DNA interaction (Figure 2) .…”

Section: (C) Extracellular Signaling Mediated By Bfgfmentioning

confidence: 98%

Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis

Ellman

Muddasani

et al. 2008

Gene

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131

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Functional components of basic fibroblast growth factor signaling that inhibit lung elastin gene expression

Cited by 25 publications

References 36 publications

Heparin-binding EGF-like growth factor regulates elastin and FGF-2 expression in pulmonary fibroblasts

Heparin-binding EGF-like growth factor regulates elastin and FGF-2 expression in pulmonary fibroblasts

Inhibition of ERK1/2 Phosphorylation: A New Strategy to Stimulate Elastogenesis in the Aorta

Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis

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