Rodent-specific hypoxia response elements enhance PAI-1 expression through HIF-1 or HIF-2 in mouse hepatoma cells

Ahn, Yongtae; Chua, Mei‐Sze; Whitlock, James P.; Shin, Yong-Chil; Song, Woon-Heung; Kim, Yongkuk; Eom, Chi-Yong; An, Won Gun

doi:10.3892/ijo_00000817

Cited by 19 publications

(17 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…; Ahn et al . ). Compared to native control mice, qRT‐PCR analyses of brain samples from injured hemispheres of 2ME2‐treated or vehicle‐treated mice revealed no changes in Serpine1 expression 15 min after TBI (primary lesion) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Among these genes, 2ME2 significantly attenuated the up-regulation of Serpine1 encoding for Plasminogen activator inhibitor 1 (PAI-1). The Serpine1 gene contains (HRE) and is induced by HIF-1a in various tissues and cell types (Kietzmann et al 2003;Liao et al 2007;Ahn et al 2010). Compared to native control mice, qRT-PCR analyses of brain samples from injured hemispheres of 2ME2-treated or vehicle-treated mice revealed no 4), and at 24 h after trauma in vehicle, low-dose (LD), and high-dose (HD) 2ME2-treated mice (n = 8/group).…”

Section: Me2 Treatment Does Not Interfere With Cns Immune Cell Infilmentioning

confidence: 99%

See 1 more Smart Citation

2‐Methoxyestradiol confers neuroprotection and inhibits a maladaptive HIF‐1α response after traumatic brain injury in mice

Schaible

Windschügl

Bobkiewicz

et al. 2014

Journal of Neurochemistry

View full text Add to dashboard Cite

HIF-1a is pivotal for cellular homeostasis in response to cerebral ischemia. Pharmacological inhibition of HIF-1a may reduce secondary brain damage by targeting post-translational mechanisms associated with its proteasomal degradation and nuclear translocation. This study examined the neuroprotective effects of 2-methoxyestradiol (2ME2), the involved HIF-1a-dependent response, and alternative splicing in exon 14 of HIF-1a (HIF-1aΔEx14) after traumatic brain injury (TBI) in mice. Intraperitoneal 2ME2 administration 30 min after TBI caused a dose-dependent reduction in secondary brain damage after 24 h. 2ME2 was physiologically tolerated, showed no effects on immune cell brain migration, and mitigated trauma-induced brain expression of neuropathologically relevant HIF-1a target genes encoding for Plasminogen activator inhibitor 1 and tumor necrosis factor alpha. Moreover, TBI-induced expression of pro-apoptotic BNIP3 was attenuated by 2ME2 treatment. Alternatively, spliced HIF-1aΔEx14 was substantially up-regulated from 6 to 48 h after TBI. In vitro, nuclear location and gene transcription activity of HIF-1aΔEx14 were impaired compared to full-length HIF-1a, but no effects on nuclear translocation of the transcriptional complex partner HIF-1b were observed. This study demonstrates that 2ME2 confers neuroprotection after TBI. While the role of alternatively spliced HIF-1aΔEx14 remains elusive, the in vivo data provide evidence that inhibition of a maladaptive HIF-1a-dependent response contributes to the neuroprotective effects of 2ME2. Keywords: 2-methoxyestradiol, alternative splicing, cerebral ischemia, HIF-1, neuroprotection, traumatic brain injury.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Me2 Treatment Does Not Interfere With Cns Immune Cell Infilmentioning

confidence: 99%

2‐Methoxyestradiol confers neuroprotection and inhibits a maladaptive HIF‐1α response after traumatic brain injury in mice

Schaible

Windschügl

Bobkiewicz

et al. 2014

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…Although a comprehensive list of HIF targets would be well beyond the scope of this article, several HIF targets that have been described in liver disease, as summarized in Table 1. Notably, the gene families represented include proinflammatory and profibrotic mediators, as well as genes involved in tumor progression 9‐17…”

Section: Hypoxic Gene Targets and Their Regulation By Hifmentioning

confidence: 99%

Hypoxia and Hypoxia Inducible Factors: Diverse Roles in Liver Diseases

2012

View full text Add to dashboard Cite

Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The Hypoxia Inducible Factors (HIFs) are a family of evolutionarily conserved transcriptional regulators that affect a homeostatic response to low oxygen tension and have been identified as key mediators of angiogenesis, inflammation, and metabolism. In this review, we summarize the evidence for a role of HIFs across a range of hepatic pathophysiology. We describe regulation of the hypoxia inducible factors and review investigations that demonstrate a role for HIFs in the development of liver fibrosis, activation of innate immune pathways, hepatocellular carcinoma, as well as other liver diseases in both human disease as well as murine models.

show abstract

“…Cobalt(II)-chloride (CoCl 2 ) binds to EPAS1 oxygen-dependent degradation domains (8), thereby inhibiting the degradation of EPAS1 and leading to the accumulation of EPAS1 protein. EPAS1 is an independent prognostic factor for cancer (9)(10)(11)(12). EPAS1 has been suggested to play a role in metastatic spread (13).…”

Section: Introductionmentioning

confidence: 99%

PLGA/poloxamer nanoparticles loaded with EPAS1 siRNA for the treatment of pancreatic cancer in vitro and in vivo

Pan

Zhu

Sun

et al. 2015

International Journal of Molecular Medicine

View full text Add to dashboard Cite

Endothelial PAS domain protein 1 (EPAS1) is a hypoxia-inducible protein that contributes to tumor progression. Hypoxia is involved in tumor aggressiveness and resistance to chemotherapy and ionizing radiation. In this study, we aimed to assess the effects of EPAS1 silencing using polyethylenimine-poly(lactide-coglycolide) (PLGA)/poloxamer nanoparticles loaded with EPAS1 siRNA on BxPC-3 pancreatic cancer cells and in a mouse model of ectopic pancreatic cancer. PLGA/poloxamer nanoparticles loaded with EPAS1 siRNA or scramble siRNA were prepared using the emulsion/solvent evaporation method. BxPC-3 pancreatic cancer cells were cultured under hypoxic conditions and treated with or without the nanoparticles. MTT and apoptosis assays were then performed. A xenograft nude mouse model of pancreatic cancer was established and the mice were treated with or without the nanoparticles. The mRNA and protein expression levels of EPAS1 in the tumor tissues were determined by semi-quantitative RT-PCR and western blot analysis, respectively. Vascular endothelial growth factor (VEGF) and tumor microvessel density indicated by CD34 were determined by immunohistochemistry. The in vitro release of EPAS1 siRNA from the nanoparticles exerted a sustained-release effect. EPAS1 siRNA nanoparticles inhibited BxPC-3 cell proliferation, and induced cell apoptosis under hypoxic conditions, compared with the nanoparticles loaded with scramble siRNA (all P<0.05). EPAS1 expression was significantly decreased in the pancreatic tumors of the mice injected with the nanoparticles loaded with EPAS1 siRNA. The pancreatic tumors of the mice injected with nanoparticles loaded with EPAS1 siRNA were significantly smaller in size and had a lower number of microvessels and a percentage of VEGF-positive cells compared with those of the mice injected with the nanoparticles loaded with scramble siRNA (all P<0.05). In conclusion, the results from the present study suggest that PLGA/poloxamer nanoparticles loaded with EPAS1 siRNA inhibit pancreatic cancer cell proliferation, induce cell apoptosis under hypoxic conditions and significantly inhibit the formation of microvessels and tumor growth in vivo.

show abstract

Rodent-specific hypoxia response elements enhance PAI-1 expression through HIF-1 or HIF-2 in mouse hepatoma cells

Cited by 19 publications

References 32 publications

2‐Methoxyestradiol confers neuroprotection and inhibits a maladaptive HIF‐1α response after traumatic brain injury in mice

2‐Methoxyestradiol confers neuroprotection and inhibits a maladaptive HIF‐1α response after traumatic brain injury in mice

Hypoxia and Hypoxia Inducible Factors: Diverse Roles in Liver Diseases

PLGA/poloxamer nanoparticles loaded with EPAS1 siRNA for the treatment of pancreatic cancer in vitro and in vivo

Contact Info

Product

Resources

About