Effect of heme and heme oxygenase-1 on vascular endothelial growth factor synthesis and angiogenic potency of human keratinocytes

Jaźwa, Agnieszka; Łoboda, Agnieszka; Gołda, Sławomir; Cisowski, Jaroslaw; Szeląg, Magdalena; Загорска, Анна; Sroczyńska, Patrycja; Drukała, Justyna; Józkowicz, Alicja; Dulak, Józef

doi:10.1016/j.freeradbiomed.2005.11.016

Cited by 83 publications

(66 citation statements)

References 46 publications

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“…Its ability to stimulate synthesis of VEGF was evidenced in cultured vascular smooth muscles, 18 microvascular endothelium, 12 and keratinocytes. 21 Likewise, in the present experiments we showed that overexpression of HO-1 increased angiogenic potential of melanoma cells because conditioned medium harvested from B16-HO-1 were stronger inducers of endothelial proliferation and formation of capillaries than those from B16-WT. However, this was not associated with up-regulation of VEGF.…”

Section: Discussionsupporting

confidence: 76%

Overexpression of Heme Oxygenase-1 in Murine Melanoma

Waś

Cichoń²,

Smolarczyk³

et al. 2006

The American Journal of Pathology

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172

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Heme oxygenases (HOs) catalyze the oxidation of heme to the biologically active products carbon monoxide (CO), biliverdin, and ferrous iron. Two distinct variants of HOs have been described in humans and rodents, each encoded by a different gene: HO-2, which is constitutively expressed, and HO-1, which is potently induced in many cell types by heme, inflammatory cytokines, and oxidative stress-related factors.

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Section: Discussionsupporting

confidence: 76%

Overexpression of Heme Oxygenase-1 in Murine Melanoma

Waś

Cichoń²,

Smolarczyk³

et al. 2006

The American Journal of Pathology

Self Cite

172

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“…4,6,7 HO-1 may also be important in cardiovascular disease and in apoptosis, 5,9,19,20 and there is also evidence that HO-1 may be linked experimentally to angiogenesis via VEGF. [10][11][12]18,21 It is therefore notable that we report good correlations between HO-1 and VEGF (r40.52) (although we acknowledge the possibility of small number error) in the absence of cancer, but that this correlation in markedly weaker in the presence of cancer (r ¼ 0.12). The reasons for this are unclear although it is tempting to speculate a linked role for HO-1 and VEGF in physiology that is uncoupled in cancer.…”

Section: Discussionmentioning

confidence: 59%

Increased levels of plasma haemoxygenase-1 in prostate cancer

Blann

Balakrishnan

Ryan

et al. 2011

Prostate Cancer Prostatic Dis

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Angiogenesis, a key component of cancer, may be driven by angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and angiopoietin-2. Haemoxygenase-1 (HO-1), a haemdegrading enzyme, may have alternative roles in angiogenesis. Levels of plasma HO-1 have not been reported in prostate cancer. We tested the hypothesis of abnormal HO-1 in 30 men with early prostate cancer, compared with 22 men with benign prostate disease (BPD) and 26 men free of prostate disease, and that HO-1 levels would correlate with VEGF, angiopoietin-2, von Willebrand factor (vWf, marking endothelial perturbation) and PSA. Plasma HO-1 was twofold higher in prostate cancer than in the two control groups, while vWf, VEGF and PSA were also raised (all Po0.02). In the subjects free of prostate disease and in the BPD groups, HO-1 correlated significantly with VEGF (r40.5, Po0.02) but the correlation in prostate cancer was not significant (r ¼ 0.117, P ¼ 0.537). There were no correlations with PSA or the Gleason stage. We conclude that HO-1 is associated with VEGF in health and BPD, but in the presence of prostate cancer, raised levels of both HO-1 and VEGF fail to correlate. This observation may have implications for the pathogenesis of prostate cancer.

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“…In fact, this miRNA promotes both in vitro and in vivo angiogenesis by activating the HO-1/HIF-a/ VEGF axis via Cul3 targeting. In keeping with these findings, several lines of evidence also show that hypoxia and hemin (an inducer of HO-1) induce HO-1 expression and concomitant augmentation of VEGF production, which enhances EC proliferation and in vitro capillary formation (18,32). In addition, hemin-induced VEGF production and angiogenesis were not elicited in normal ECs by co-treatment with the HO-1 inhibitor (20) or in ECs from HO-1 -/ -mice (16), strongly implicating a role of HO-1 byproducts in angiogenesis.…”

Section: Discussionmentioning

confidence: 63%

“…In fact, functional inhibition of Cul3 effectively stabilizes the transcription factor Nrf2 (21). Importantly, a wide range of evidence shows that Nrf2 is an important transcription factor for phase II genes, including HO-1, which promotes angiogenesis and survival of ECs by increasing VEGF expression (32,33). Here, we provide evidence that hypoxia-inducible miR-101 inhibits Cul3 expression by directly targeting its 3¢UTR, leading to upregulation of Nrf2-mediated HO-1 expression and concomitant promotion of angiogenesis.…”

Section: Discussionmentioning

confidence: 67%

Hypoxia-Responsive MicroRNA-101 Promotes Angiogenesis via Heme Oxygenase-1/Vascular Endothelial Growth Factor Axis by Targeting Cullin 3

Kim

Lee

et al. 2014

Antioxidants & Redox Signaling

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Aims: Hypoxia induces expression of various genes and microRNAs (miRs) that regulate angiogenesis and vascular function. In this study, we investigated a new functional role of new hypoxia-responsive miR-101 in angiogenesis and its underlying mechanism for regulating heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) expression. Results: We found that hypoxia induced miR-101, which binds to the 3¢untranslated region of cullin 3 (Cul3) and stabilizes nuclear factor erythroid-derived 2-related factor 2 (Nrf2) via inhibition of the proteasomal degradation pathway. miR-101 overexpression promoted Nrf2 nuclear accumulation, which was accompanied with increases in HO-1 induction, VEGF expression, and endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) production. The elevated NO-induced S-nitrosylation of Kelch-like ECH-associated protein 1 and subsequent induction of Nrf2-dependent HO-1 lead to further elevation of VEGF production via a positive feedback loop between the Nrf2/HO-1 and VEGF/eNOS axes. Moreover, miR-101 promoted angiogenic signals and angiogenesis both in vitro and in vivo, and these events were attenuated by inhibiting the biological activity of HO-1, VEGF, or eNOS. Moreover, these effects were also observed in aortic rings from HO-1 +/ -and eNOS -/ -mice. Local overexpression of miR-101 improved therapeutic angiogenesis and perfusion recovery in the ischemic mouse hindlimb, whereas antagomiR-101 diminished regional blood flow. Innovation: Hypoxia-responsive miR-101 stimulates angiogenesis by activating the HO-1/VEGF/eNOS axis via Cul3 targeting. Thus, miR-101 is a novel angiomir. Conclusion: Our results provide new mechanistic insights into a functional role of miR-101 as a potential therapeutic target in angiogenesis and vascular remodeling. Antioxid. Redox Signal. 21, 2469-2482.

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Effect of heme and heme oxygenase-1 on vascular endothelial growth factor synthesis and angiogenic potency of human keratinocytes

Abstract: Background: Skin injury leads to the release of heme, a potent prooxidant which is degraded by

Cited by 83 publications

References 46 publications

Overexpression of Heme Oxygenase-1 in Murine Melanoma

Overexpression of Heme Oxygenase-1 in Murine Melanoma

Increased levels of plasma haemoxygenase-1 in prostate cancer

Hypoxia-Responsive MicroRNA-101 Promotes Angiogenesis via Heme Oxygenase-1/Vascular Endothelial Growth Factor Axis by Targeting Cullin 3

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