Cutaneous hypoxia in patients with systemic sclerosis (scleroderma)

Silverstein, J. L.

doi:10.1001/archderm.124.9.1379

Cited by 30 publications

(18 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, human dermal fibroblasts cultured in hypoxic conditions exhibit an increased TGF-␤RI to RII ratio. Therefore, the increased RI/RII ratio that we observe in the majority of SSc fibroblasts derived from patients with early disease may be a manifestation of the hypoxic environment that is present in SSc skin due to the vascular damage associated with this disease (46). The observed alterations of TGF-␤ receptor levels, together with the mechanistic insights described in this study, suggest that the modulation of the RI to RII ratio may represent a novel mode of diversifying TGF-␤ signaling and its biologic effects, which occurs both in physiologic and pathologic conditions.…”

Section: Discussionmentioning

confidence: 82%

Transforming Growth Factor-β Receptor Type I-dependent Fibrogenic Gene Program Is Mediated via Activation of Smad1 and ERK1/2 Pathways

Pannu

Nakerakanti

Smith

et al. 2007

Journal of Biological Chemistry

182

142

View full text Add to dashboard Cite

The transforming growth factor (TGF)-␤/Smad3 signaling pathway is considered a central mediator of pathological organ fibrosis; however, contribution of Smad2/3-independent TGF-␤ signaling has not been fully explored. The present study utilized previously a described model of scleroderma (SSc) fibrosis based on forced expression of the TGF-␤RI (ALK5) (Pannu, J., Gardner, H., Shearstone, J. R., Smith, E., and Trojanowska, M. (2006) Arthritis Rheum. 54, 3011-3021). This study was aimed at determining the molecular mechanisms underlying the profibrotic program in this model. We demonstrate that the TGF-␤RI-dependent up-regulation of collagen and CCN2 (CTGF) does not involve Smad2/3 activation but is mediated by ALK1/Smad1 and ERK1/2 pathways. The following findings support this conclusion: (i) Smad2 and -3 were not phosphorylated in response to TGF-␤RI, (ii) a TGF-␤RI mutant defective in Smad2/3 activation, ALK5(3A), potently stimulated collagen production, (iii) elevation of TGF-␤RI triggered sustained association of ALK5 with ALK1 and high levels of Smad1 phosphorylation, (iv) blockade of Smad1 via small interfering RNA abrogated collagen and CCN2 up-regulation in this model, (v) elevated TGF-␤RI led to a prolonged activation of ERK1/2, (vi) the pharmacologic inhibitor of ERK1/2 inhibited Smad1 phosphorylation and abrogated profibrotic effects of elevated TGF␤-RI. Additional experiments demonstrated that a GC-rich response element located ؊6 to ؊16 (upstream of the transcription start site) in the CCN2 promoter mediated Smad1-dependent increased promoter activity in this model. This element was shown previously to mediate up-regulation of the CCN2 promoter in SSc fibroblasts. In conclusion, this study defines a novel ALK1/Smad1-and ERK1/2-dependent, Smad3-independent mode of TGF-␤ signaling that may operate during chronic stages of fibrosis in SSc.

show abstract

Section: Discussionmentioning

confidence: 82%

Transforming Growth Factor-β Receptor Type I-dependent Fibrogenic Gene Program Is Mediated via Activation of Smad1 and ERK1/2 Pathways

Pannu

Nakerakanti

Smith

et al. 2007

Journal of Biological Chemistry

182

142

View full text Add to dashboard Cite

show abstract

“…VSM cells transiently transfected with the appropriate CAT construct were exposed to 20% O 2 or 1% O 2 for 24 h and then analyzed for CAT activity. The data represent the average value from three independent experiments and the mean fold induction of CAT activity in extracts of cells exposed to 1% O 2 and cadmium (22). Neither the AB1 enhancer nor the SX2 enhancer (Fig.…”

Section: Induction Of Ho-1 Expression In Vsm Cellsmentioning

confidence: 99%

“…Low cellular oxygen tension is a feature of both physiological conditions, such as adaptations to high altitude and physical endurance exercise (1), and pathophysiological conditions including ischemia, fibrosis (2), and neoplasia (3). Mammalian cells respond to hypoxia in part by increased expression of several genes that encode both tissue-specific and ubiquitous proteins (4).…”

mentioning

confidence: 99%

Hypoxia-inducible Factor-1 Mediates Transcriptional Activation of the Heme Oxygenase-1 Gene in Response to Hypoxia

Lee

Jiang

Chin

et al. 1997

Journal of Biological Chemistry

728

408

View full text Add to dashboard Cite

Exposure of rats to hypoxia (7% O2Low cellular oxygen tension is a feature of both physiological conditions, such as adaptations to high altitude and physical endurance exercise (1), and pathophysiological conditions including ischemia, fibrosis (2), and neoplasia (3). Mammalian cells respond to hypoxia in part by increased expression of several genes that encode both tissue-specific and ubiquitous proteins (4). These proteins participate in diverse biological processes including erythropoiesis, which enhances the oxygen carrying capacity of the blood; angiogenesis, which permits delivery of oxygen carrying blood to hypoxic sites; glycolysis, as a means of energy production; xenobiotic detoxification; and cellular adaptation to stress. Hypoxia-inducible proteins within these respective categories include erythropoietin (EPO) 1 (5), vascular endothelial growth factor (6), glycolytic enzymes (7-9), NAD(P)H:quinone oxidoreductase (10), and heat shock proteins (11,12). Where examined, increased expression of specific proteins in response to hypoxia is regulated primarily at the level of gene transcription (although posttranscriptional mechanisms have also been characterized).Another stress-associated protein whose expression is stimulated by hypoxia is heme oxygenase-1 (HO-1) (13, 14). HO-1, a microsomal membrane enzyme, catalyzes the first and ratelimiting reaction in heme catabolism, the oxidative cleavage of b-type heme molecules to yield equimolar quantities of biliverdin, carbon monoxide (CO), and iron. Biliverdin is subsequently converted to bilirubin by the action of biliverdin reductase. The expression of HO-1 is dramatically induced not only by the substrate, heme, but a variety of stress-associated agents, including heavy metals, hyperthermia, and UV irradiation (reviewed in Maines (15)). A common feature among these inducers, including heme, is that they generate reactive oxygen species and/or diminish glutathione levels. This correlation and the observation that bilirubin functions as an antioxidant (16) has led to the hypothesis that induction of HO-1 is part of a general response to oxidant stress and that this enzyme plays a protective role during such conditions (17)(18)(19).Stimulation of HO-1 expression by most if not all inducers is controlled primarily at the level of gene transcription and in our studies on the regulation of the mouse HO-1 gene, we have identified two 5Ј distal enhancer regions, SX2 and AB1, that mediate gene activation by a variety of pro-oxidants including heme, heavy metals, TPA, hydrogen peroxide, and LPS (20 -23). The mechanism of HO-1 induction by hypoxia has not been investigated and because this induction has been proposed to occur as a consequence of oxidative stress (13), we examined the role of the SX2 and AB1 enhancers in hypoxia-dependent gene activation. In this report we show that these enhancers do not mediate transcriptional activation of the HO-1 gene in response to hypoxia. Rather, this induction is mediated by a 163-bp fragment located directly downstream of ...

show abstract

“…Hypoxia is thought to play a critical role in SSc. SSc-associated microangiopathy results in a disturbed blood flow in the capillaries with consequent hypoxia, which is likely to be aggravated by tissue fibrosis [169][170][171][172]. Hypoxia alters vascular endothelium but also directly activates platelets [173,174] (our unpublished results).…”

Section: Potential Mechanisms Mediating Platelet Activation In Sscmentioning

confidence: 67%

Blood Platelets and Systemic Sclerosis

Lepreux¹,

Solanilla²,

Villeneuve³

et al. 2012

Systemic Sclerosis - An Update on the Aberrant Immune System and Clinical Features

View full text Add to dashboard Cite

Cutaneous hypoxia in patients with systemic sclerosis (scleroderma)

Cited by 30 publications

References 0 publications

Transforming Growth Factor-β Receptor Type I-dependent Fibrogenic Gene Program Is Mediated via Activation of Smad1 and ERK1/2 Pathways

Transforming Growth Factor-β Receptor Type I-dependent Fibrogenic Gene Program Is Mediated via Activation of Smad1 and ERK1/2 Pathways

Hypoxia-inducible Factor-1 Mediates Transcriptional Activation of the Heme Oxygenase-1 Gene in Response to Hypoxia

Blood Platelets and Systemic Sclerosis

Contact Info

Product

Resources

About