Jozef Dulak

Jagiellonian University, Cracovia, Lesser Poland Voivodeship, Poland

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Publications (195)852.77 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Blood vessel formation is a fundamental process for the development of organism and tissue regeneration. Of importance, angiogenesis occurring during postnatal development is usually connected with inflammation. Here, we review how molecular and cellular mechanisms underlying inflammatory reactions regulate angiogenesis. Inflamed tissues are characterized by hypoxic conditions and immune cell infiltration. In this review, we describe an interplay of hypoxia-inducible factors (HIFs), HIF1 and HIF2, as well as NF-κB and nitric oxide in the regulation of angiogenesis. The mobilization of macrophages and the differential role of M1 and M2 macrophage subsets in angiogenesis are also discussed. Next, we present the current knowledge about microRNA regulation of inflammation in the context of new blood vessel formation. Finally, we describe how the mechanisms involved in inflammation influence tumor angiogenesis. We underlay and discuss the role of NF-E2-related factor 2/heme oxygenase-1 pathway as crucial in the regulation of inflammation-induced angiogenesis. © 2015 IUBMB Life, 2015. © 2015 International Union of Biochemistry and Molecular Biology.
    International Union of Biochemistry and Molecular Biology Life 04/2015; 67(3). DOI:10.1002/iub.1358 · 2.76 Impact Factor
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    ABSTRACT: Diabetes is associated with reduced expression of heme oxygenase-1 (HO-1), a heme-degrading enzyme of cytoprotective and proangiogenic properties. In myoblasts and satellite cells (mSCs) HO-1 improves survival, proliferation and production of proangiogenic growth factors. Induction of HO-1 in injured tissues facilitates neovascularization, the process impaired in diabetes. We aimed to examine whether conditioned media from the HO-1 overexpressing myoblast cell line can improve a blood-flow recovery in ischemic muscles of diabetic mice. Analysis of myogenic markers was performed at mRNA level in primary mSCs, isolated by a pre-plate technique from diabetic db/db and normoglycemic wild type mice, and then cultured under growth or differentiation conditions. Hind limb ischemia was performed by femoral artery ligation in db/db mice and blood recovery was monitored by Laser Doppler measurements. Mice were treated with a single intramuscular injection of conditioned media harvested from wild type C2C12 myoblast cell line, C2C12 cells stably transduced with HO-1 cDNA or with unconditioned media. Expression of HO-1 was lower in mSCs isolated from muscles of diabetic db/db mice when compared to their wild type counterparts, what was accompanied by increased levels of Myf5 or CXCR4, and decreased Mef2 or Pax7. Such cells displayed also diminished differentiation potential when cultured in vitro, as shown by less effective formation of myotubes and reduced expression of myogenic markers (myoD, myogenin, and myosin). Blood flow recovery after induction of severe hind limb ischemia was delayed in db/db mice compared to that in normoglycemic individuals. To improve muscle regeneration after ischemia, conditioned media collected from differentiating C2C12 cells (control and HO-1 overexpressing) were injected into hind limbs of diabetic mice. Analysis of blood flow revealed that media from HO-1 overexpressing cells accelerated blood-flow recovery, while immunohistochemical staining assessment of vessels density in injected muscle confirmed increased angiogenesis. The effect might be mediated by SDF-1α proangiogenic factor, as its secretion is elevated in HO-1 overexpressing cells. In conclusion, paracrine stimulation of angiogenesis in ischemic skeletal muscle using conditioned media may be a safe approach exploiting protective and proangiogenic properties of HO-1 in diabetes.
    Stem Cell Research & Therapy 04/2015; 6(1):61. DOI:10.1186/s13287-015-0063-8 · 4.63 Impact Factor
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    ABSTRACT: Heme oxygenase-1 (HO-1) mitigates cellular injury by antioxidant, anti-apoptotic, anti-inflammatory and proangiogenic effects. Vascular endothelial growth factor (VEGF) is a critical regulator of blood vessels growth. Their coordinated action was analyzed in a model of femoral artery ligation (FAL) in mice lacking HO-1 gene (HO-1 KO). Gastrocnemius skeletal muscles of HO-1 KO mice were preemptively injected with plasmids containing hypoxia-response element (HRE) driving the expression of only HO-1 (pHRE-HO1) or both HO-1 and VEGF (pHRE-HO1-VEGF). At day 14th the pHRE-HO1 vector increased an impaired post-ischemic blood flow recovery in HO-1 KO mice to the level observed in wild-type (WT) mice subjected to FAL and pHRE-HO1-VEGF restored it already at day 7. The pHRE-HO1 gene therapy diminished, when compared to control pHRE-empty-treated HO-1 KO mice, the expression of toll-like receptors (TLR4 and TLR9) and inflammatory cytokines (IL-1β, IL-6 and TNFα) at day 3, whereas opposite effects were observed following concomitant HO-1 and VEGF gene transfer. Moreover, HO-1 diminished ischemia-induced expression of MyoD involved in satellite cell differentiation in HO-1 KO mice. Our results confirm the therapeutic potential of HO-1 and VEGF against critical limb ischemia although, their concomitant delivery may have contradictory actions on the resolution of inflammation. Copyright © 2015. Published by Elsevier Inc.
    Vascular Pharmacology 04/2015; DOI:10.1016/j.vph.2015.02.011 · 4.62 Impact Factor
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    Scientific Reports 02/2015; · 5.08 Impact Factor
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    ABSTRACT: Mouse and human induced pluripotent stem cells (iPSCs) may represent a novel approach for modeling diabetes. Taking this into consideration, the aim of this study was to generate and evaluate differentiation potential of iPSCs from lep(db/db) (db/db) mice, the model of diabetes type 2 as well as from patients with Maturity Onset Diabetes of the Young 3 (HNF1A MODY). Murine iPSC colonies from both wild type and db/db mice were positive for markers of pluripotency: Oct3/4A, Nanog, SSEA1, CDy1 and alkaline phosphatase and differentiated in vitro and in vivo into cells originating from three germ layers. However, our results suggest impaired differentiation of db/db cells into endothelial progenitor-like cells expressing CD34 and Tie2 markers and their reduced angiogenic potential. Human control and HNF1A MODY reprogrammed cells also expressed pluripotency markers: OCT3/4A, SSEA4, TRA-1-60, TRA-1-81, formed embryoid bodies (EBs) and differentiated into cells of three germ layers. Additionally, insulin expressing cells were obtained from those partially reprogrammed cells with direct as well as EB-mediated differentiation method. Our findings indicate that disease-specific iPSCs may help to better understand the mechanisms responsible for defective insulin production or vascular dysfunction upon differentiation toward cell types affected by diabetes.
    Scientific Reports 02/2015; 5:8597. DOI:10.1038/srep08597 · 5.08 Impact Factor
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    ABSTRACT: C57BL/6 is the most often used laboratory mouse strain. However, sometimes it is beneficial to cross the transgenic mice on the C57BL/6 background to the other strain, such as FVB. Although this is a common strategy, the influence of crossing these different strains on homeostatic expression of cytokines is not known. Here we have investigated the differences in the expression of selected cytokines between C57BL/6J and C57BL/6JxFVB mice in serum and skeletal muscle. We have found that only few cytokines were altered by crossing of the strains. Concentrations of IL5, IL7, LIF, MIP-2, and IP-10 were higher in serum of C57BL/6J mice than in C57BL/6JxFVB mice, whereas concentration of G-CSF was lower in C57BL/6J. In the skeletal muscle only the concentration of VEGF was higher in C57BL/6J mice than in C57BL/6JxFVB mice. Concluding, the differences in cytokine expression upon crossing C57BL/6 and FVB strain in basal conditions are not profound.
    Mediators of Inflammation 01/2015; 2015:762419. DOI:10.1155/2015/762419 · 2.42 Impact Factor
  • Toxicology 12/2014; 328. DOI:10.1016/j.tox.2014.12.002 · 3.75 Impact Factor
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    ABSTRACT: Background Peroxisome proliferator-activated receptor-¿ (PPAR¿) agonists, which have been used as insulin sensitizers in diabetic patients, may improve functions of endothelial cells (ECs). We investigated the effect of PPAR¿ on angiogenic activities of murine ECs and bone marrow-derived proangiogenic cells (PACs).MethodsPACs were isolated from bone marrow of 10¿12 weeks old, wild type, db/db and PPAR¿ heterozygous animals. Cells were cultured on fibronectin and gelatin coated dishes in EGM-2MV medium. For in vitro stimulations, rosiglitazone (10 ¿mol/L) or GW9662 (10 ¿mol/L) were added to 80% confluent cell cultures for 24 hours. Angiogenic potential of PACs and ECs was tested in vitro and in vivo in wound healing assay and hind limb ischemia model.ResultsECs and PACs isolated from diabetic db/db mice displayed a reduced angiogenic potential in ex vivo and in vitro assays, the effect partially rescued by incubation of cells with rosiglitazone (PPAR¿ activator). Correction of diabetes by administration of rosiglitazone in vivo did not improve angiogenic potential of isolated PACs or ECs. In a hind limb ischemia model we demonstrated that local injection of conditioned media harvested from wild type PACs improved the blood flow restoration in db/db mice, confirming the importance of paracrine action of the bone marrow-derived cells.Transcriptome analysis showed an upregulation of prooxidative and proinflammatory pathways, and downregulation of several proangiogenic genes in db/db PACs. Interestingly, db/db PACs had also a decreased level of PPAR¿ and changed expression of PPAR¿-regulated genes. Using normoglycemic PPAR¿+/¿ mice we demonstrated that reduced expression of PPAR¿ does not influence neovascularization either in wound healing or in hind limb ischemia models.Conclusions In summary, activation of PPAR¿ by rosiglitazone improves angiogenic potential of diabetic ECs and PACs, but decreased expression of PPAR¿ in diabetes does not impair angiogenesis.
    Cardiovascular Diabetology 11/2014; 13(1):150. DOI:10.1186/PREACCEPT-1453357592137930 · 3.71 Impact Factor
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    ABSTRACT: Sarcoidosis is a granulomatous disease of unknown etiology. The disease has an important inflammatory and immune component; however, its immunopathogenesis is not completely understood. Recently, the role of microRNAs (miRNAs), the small non-coding RNAs, has attracted attention as both being involved in pathogenesis and serving as disease markers. Accordingly, changes in the expression of some miRNAs have been also associated with different autoimmune pathologies. However, not much is known about the role of miRNAs in sarcoidosis. Therefore, the aim of this study was to compare the level of expression of selected miRNAs in healthy individuals and patients with sarcoidosis. We detected significantly increased level of miR-34a in peripheral blood mononuclear cells isolated from sarcoidosis patients. Moreover, significantly up-regulated levels of interferon (IFN)-γ, IFN-γ inducible protein (IP-10) and vascular endothelial growth factor were detected in sera of patients when compared to healthy subjects. Our results add to a known inflammatory component in sarcoidosis. Changes in the levels of miR-34a may suggest its involvement in the pathology of this disease.
    Archivum Immunologiae et Therapiae Experimentalis 11/2014; 63(2). DOI:10.1007/s00005-014-0315-9 · 2.82 Impact Factor
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    ABSTRACT: Rhabdomyosarcoma is the most common type of soft tissue sarcoma in children. Two main subtypes of rhabdomyosarcoma with different molecular pattern and distinct clinical behaviour may be identified-embryonal and alveolar rhabdomyosarcoma. All types of rhabdomyosarcoma are believed to be of myogenic origin as they express high levels of myogenesis-related factors. They all, however, fail to undergo a terminal differentiation which results in tumour formation. In the aberrant regulation of myogenesis in rhabdomyosarcoma, microRNAs and epigenetic factors are particularly involved. Indeed, these mediators seem to be even more significant for the development of rhabdomyosarcoma than canonical myogenic transcription factors like MyoD, a master regulatory switch for myogenesis. Therefore, in this review we focus on the regulation of rhabdomyosarcoma progression by microRNAs, and especially on microRNAs of the myo-miRNAs family (miR-1, -133a/b and -206), other well-known myogenic regulators like miR-29, and on microRNAs recently recognized to play a role in the differentiation of rhabdomyosarcoma, such as miR-450b-5p or miR-203. We also review changes in epigenetic modifiers associated with rhabdomyosarcoma, namely histone deacetylases and methyltransferases, especially from the Polycomp Group, like Yin Yang1 and Enhancer of Zeste Homolog2. Finally, we summarize how the functioning of these molecules can be affected by oxidative stress and how antioxidative enzymes can influence the development of this tumour.
    The international journal of biochemistry & cell biology 05/2014; 53. DOI:10.1016/j.biocel.2014.05.003 · 4.24 Impact Factor
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    ABSTRACT: Proangiogenic enzyme thymidine phosphorylase (TP) is a promising target for anticancer therapy, yet its action in non-small cell lung carcinoma (NSCLC) is not fully understood. To elucidate its role in NSCLC tumor growth, NCI-H292 lung mucoepidermoid carcinoma cells and endothelial cells were engineered to overexpress TP by viral vector transduction. NSCLC cells with altered expression of transcription factor Nrf2 or its target gene heme oxygenase-1 (HO-1) were used to study the regulation of TP and the findings from pre-clinical models were related to gene expression data from clinical NSCLC specimens. Overexpression of Nrf2 or HO-1 resulted in upregulation of TP in NCI-H292 cells, an effect mimicked by treatment with an antioxidant N-acetylcysteine and partially reversed by HO-1 knockdown. Overexpression of TP attenuated cell proliferation and migration in vitro, but simultaneously enhanced angiogenic potential of cancer cells supplemented with thymidine. The latter was also observed for SK-MES-1 squamous cell carcinoma and NCI-H460 large cell carcinoma cells. TP-overexpressing NCI-H292 tumors in vivo exhibited better oxygenation and higher expression of IL-8, IL-1β and IL-6. TP overexpression in endothelial cells augmented their angiogenic properties which was associated with enhanced generation of HO-1 and VEGF. Correlation of TP with the expression of HO-1 and inflammatory cytokines was confirmed in clinical samples of NSCLC. Altogether, the increased expression of IL-1β and IL-6 together with proangiogenic effects of TP-expressing NSCLC on endothelium can contribute to tumor growth, implying TP as a target for antiangiogenesis in NSCLC.
    PLoS ONE 05/2014; 9(5):e97070. DOI:10.1371/journal.pone.0097070 · 3.53 Impact Factor
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    ABSTRACT: In their recent paper published in Stem Cells and Development Suszynska et al. (Stem Cells Dev 2013 Dec 3. [Epub ahead of print]) discussed the strategies of analysing the so called very small embryonic-like cells (VSELs), defined as Lin<sup>-</sup>Sca-1<sup>+</sup>CD45<sup>-</sup>FSC<sup>low</sup>, which were claimed to be the pluripotent stem cells present in the bone marrow. In their text Suszynska et al. have cited our recent study published in PLoS One (Szade et al. PloS One 2013: 8: e63329), in which we undermined the stem cells characteristics of VSELs. The analysis performed by Suszynska et al. contains several statements we believe are misleading and we comment on them here.
    Stem cells and development 03/2014; DOI:10.1089/scd.2014.0028 · 4.20 Impact Factor
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    ABSTRACT: AbstractAims/IntroductionType 2 diabetes is often complicated by diabetic foot syndrome (DFS). We analyzed the circulating stem cells, growth factor and anti‐oxidant gene expression profiles in type 2 diabetes patients without or with different forms of DFS.Materials and MethodsHealthy volunteers (n = 13) and type 2 diabetes patients: (i) without DFS (n = 10); or with (ii) Charcot osteoneuropathy (n = 10); (iii) non‐infected (n = 17); (iv) infected (n = 11); and (v) healed ulceration were examined (n = 12). Peripheral blood endothelial progenitor cells (EPC), mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and very small embryonic‐like (VSEL) cells were phenotyped using flow cytometry. Plasma cytokine concentrations and gene expressions in blood cells were measured by Luminex and quantitative real‐time polymerase chain reaction assays, respectively.ResultsPatients with non‐complicated type 2 diabetes showed reduced HMOX1 expression, accompanied by HMOX2 upregulation, and had less circulating EPC, MSC or HSC than healthy subjects. In contrast, VSEL cells were elevated in the type 2 diabetes group. However, subjects with DFS, even with healed ulceration, had fewer VSEL cells, more CD45‐CD29+CD90+MSC, and upregulated HMOX1 when compared with the type 2 diabetes group. Patients with Charcot osteopathy had lowered plasma fibroblast growth factor‐2. Elevated plasma tumor necrosis factor‐α and decreased catalase expression was found in all diabetic patients.ConclusionsPatients with type 2 diabetes and different forms of DFS have an altered number of circulating stem cells. Type 2 diabetes might also be associated with a changed plasma growth factor and anti‐oxidant gene expression profile. Altogether, these factors could contribute to the pathogenesis of different forms of DFS.
    Journal of Diabetes Investigstion 02/2014; 5(1):99-107. DOI:10.1111/jdi.12131 · 1.50 Impact Factor
  • Jozef Dulak, Alicja Jozkowicz
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    ABSTRACT: Not only double, Janus face, but numerous appearances characterize heme oxygenase-1 (HO-1), an inducible enzyme which main role is to degrade heme. Recently, the non-canonical functions of HO-1 have particularly attracted researchers' attention. Indeed, understanding the enzyme-independent activities of HO-1 can provide additional chances for translational application of research on HO-1. In this Forum Issue eight reviews and two original papers describe a plethora of mechanisms in which this pleiotropic protein is involved. Further understanding of HO-1 functions is of particular significance for elucidating the pathology of various human diseases and providing rationale for novel therapies.
    Antioxidants & Redox Signaling 12/2013; 20(11). DOI:10.1089/ars.2013.5761 · 7.67 Impact Factor
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    ABSTRACT: Purpose. Retinal degenerative diseases targeting the retinal pigment epithelium (RPE) and adjacent photoreceptors affect millions of people worldwide. The field of stem cell- and gene-based therapy holds great potential for the treatment of such diseases. The present study sought to graft genetically engineered mesenchymal stem cells (MSCs) that continuously produce neurotrophin-4 (NT-4) into the murine eye after the onset of acute retinal injury. Methods. C57BL/6 mice were subjected to acute retinal damage using a low dose of sodium iodate (20 mg/kg of body weight), followed by intravitreal injection of lentivirally modified MSCs-NT-4 into the right eye. At 3 months after the MSC transplantation grafted cell survival, retinal function and gene expression were analyzed. Results. Immunofluorescence analysis confirmed that transplanted MSCs survived for at least 3 months after intravitreal injection and preferentially migrated towards sites of injury within the retina. MSC-NT-4 actively produced NT-4 in the injured retina and significantly protected damaged retinal cells, as evaluated by electroretinography (ERG) and optical coherence tomography (OCT). Importantly, the long-term therapy with MSCs-NT-4 was also associated with induction of prosurvival signaling, considerable overexpression of some subsets of transcripts, including several members of the crystallin β-γ superfamily (Cryba4, Crybb3, Cryba2, Crybb1, Crybb2, Cryba1, Crygc) and significant upregulation of biological processes associated with visual perception, sensory perception of light stimulus, eye development, sensory organ development, and system development. Conclusions. Transplantation of genetically modified MSCs that produce neurotrophic growth factors may represent a useful strategy for treatment of different forms of retinopathies in the future.
    Investigative ophthalmology & visual science 11/2013; 54(13). DOI:10.1167/iovs.13-12221 · 3.66 Impact Factor
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    ABSTRACT: Aims: Heme oxygenase-1 (HO-1) is a cytoprotective enzyme, which can be downregulated in diabetes. Its importance for mature endothelium has been described, but a role in proangiogenic progenitors is not well known. We investigated the effect of HO-1 on angiogenic potential of bone marrow-derived cells (BMDCs) and on blood flow recovery in ischemic muscle of diabetic mice. Results: Lack of HO-1 decreased the number of endothelial progenitor cells (Lin-CD45-cKit-Sca-1+VEGFR-2+) in murine bone marrow, and inhibited the angiogenic potential of cultured BMDCs, affecting their survival under oxidative stress, proliferation, migration, formation of capillaries, and paracrine proangiogenic potential. Transcriptome analysis of HO-1-/- BMDCs revealed the attenuated upregulation of proangiogenic genes in response to hypoxia. Heterozygous HO-1+/- diabetic mice subjected to hind limb ischemia showed the reduced local expression of VEGF, PlGF, SDF-1, VEGFR-1, VEGFR-2, CXCR-4. This was accompanied by impaired revascularization of ischemic muscle, despite a strong mobilization of bone marrow-derived proangiogenic progenitors (Sca-1+CXCR-4+) into peripheral blood. Blood flow recovery could be rescued by local injections of conditioned media harvested from BMDCs, but not by injection of cultured BMDCs. Innovation: This is the first report showing that HO-1 haploinsufficiency impairs tissue revascularization in diabetes and that proangiogenic in situ response, not progenitor cell mobilization, is important for blood flow recovery. Conclusions: HO-1 is necessary for a proper proangiogenic function of BMDCs. Low level of HO-1 in hyperglycemic mice decreases restoration of perfusion in ischemic muscle, what can be rescued by local injection of conditioned media from cultured BMDCs.
    Antioxidants & Redox Signaling 11/2013; 20(11). DOI:10.1089/ars.2013.5426 · 7.67 Impact Factor
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    ABSTRACT: Vascular endothelial growth factors (VEGFs) are found at high levels in hypoxic tumors. As major components directing pathologic neo-vascularisation, they regulate stromal reactions. Consequently, novel strategies, targeting and inhibiting VEGF over-production upon hypoxia offer considerable potential for modern anti-cancer therapies controlling rather than destroying tumor angiogenesis. Here we report the design of a vector expressing the soluble form of VEGF receptor-2 (sVEGFR2) driven by a hypoxia responsive element (HRE)-regulated promoter. To enable in vivo imaging by infrared visualization, mCherry and IFP1.4 coding sequences were built into the vector. Plasmid construction was validated through transfection into embryonic human kidney HEK293 and murine B16F10 melanoma cells. sVEGFR2 was expressed in hypoxic conditions only, confirming that the gene was regulated by the HRE-promoter. sVEGFR2 was found to bind efficiently and specifically to murine and human VEGF-A, reducing the growth of tumor and endothelial cells as well as impacting angiogenesis in vitro. The hypoxia-conditioned sVEGFR2 expression was shown to be functional in vivo: tumor angiogenesis was inhibited and, on stable transfection of B16F10 melanoma cells, tumor growth was reduced. Enhanced expression of sVEGFR2 was accompanied by a modulation in levels of VEGF-A. The resulting balance reflected the effect on tumor growth and on the control of angiogenesis. A concomitant increase of intra-tumor oxygen tension also suggested an influence on vessel normalization. The possibility to express an angiogenesis regulator as sVEGFR2, in a hypoxia-conditioned manner, significantly opens new strategies for tumor vessel-controlled normalization and the novel design of adjuvants for combined cancer therapies.
    Molecular Cancer Therapeutics 10/2013; 13(1). DOI:10.1158/1535-7163.MCT-13-0637 · 6.11 Impact Factor
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    ABSTRACT: Aim: Nuclear factor E2-related factor 2 (Nrf2), a key cytoprotective transcription factor, regulates also proangiogenic mediators, IL-8 and heme oxygenase-1 (HO-1). However, hitherto its role in blood vessel formation was modestly examined. Particularly, although Nrf2 was shown to affect hematopoietic stem cells, it was not tested in bone marrow-derived proangiogenic cells (PAC). Here we investigated angiogenic properties of Nrf2 in PAC, endothelial cells and inflammation-related revascularization. Results: Treatment of endothelial cells with angiogenic cytokines increased nuclear localization of Nrf2 and induced expression of HO-1. Nrf2 activation stimulated a tube network formation, while its inhibition decreased angiogenic response of human endothelial cells, the latter effect reversed by overexpression of HO-1. Moreover, lack of Nrf2 attenuated survival, proliferation, migration and angiogenic potential of murine PAC and affected angiogenic transcriptome in vitro. Additionally, angiogenic capacity of PAC Nrf2-/- in in vivo Matrigel assay and PAC mobilization in response to hind limb ischemia of Nrf2-/- mice were impaired. Despite that, restoration of blood flow in Nrf2-deficient ischemic muscles was better and accompanied by increased oxidative stress and inflammatory response. Accordingly, anti-inflammatory agent, etodolac, tended to diminish blood flow in the Nrf2-/- mice. Innovation: Identification of a novel role of Nrf2 in angiogenic signaling of endothelial cells and PAC. Conclusion: Nrf2 contributes to angiogenic potential of both endothelial cells and PAC, however, its deficiency increases muscle blood flow under tissue ischemia. This might suggest a proangiogenic role of inflammation in the absence of Nrf2 in vivo, concomitantly undermining the role of PAC in such conditions.
    Antioxidants & Redox Signaling 09/2013; 20(11). DOI:10.1089/ars.2013.5219 · 7.67 Impact Factor
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    ABSTRACT: Heme oxygenease-1 (HO-1) converts heme to biliverdin, carbon monoxide and ferrous ions, but its cellular functions are far beyond heme metabolism. HO-1 via heme removal and degradation products acts as a cytoprotective, anti-inflammatory, immunomodulatory, and pro-angiogenic protein, regulating also a cell cycle. Additionally, HO-1 can translocate to nucleus and regulate transcription factors, so it can also act independently of enzymatic function. Recently, body of evidence has emerged indicating a role for HO-1 in postnatal differentiation of stem and progenitor cells. Maturation of satellite cells, skeletal myoblasts, adipocytes, and osteoclasts is inhibited by HO-1, whereas neurogenic differentiation and formation of cardiomyocytes perhaps can be enhanced. Moreover, HO-1 influences a lineage commitment in pluripotent stem cells and maturation of hematopoietic cells. It may play a role in development of osteoblasts, but descriptions of its exact effects are inconsistent. In this review we discuss a role of HO-1 in cell differentiation, and possible HO-1-dependent signal transduction pathways. Among the potential mediators, we focused on microRNA (miRNA). These small, noncoding RNAs are critical for cell differentiation. Recently we have found that HO-1 not only influences expression of specific miRNAs but also regulates miRNA processing enzymes. It seems that interplay between HO-1 and miRNAs may be important in regulating fates of stem and progenitor cells.
    Antioxidants & Redox Signaling 09/2013; 20(11). DOI:10.1089/ars.2013.5341 · 7.67 Impact Factor
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Publication Stats

4k Citations
852.77 Total Impact Points


  • 1998–2015
    • Jagiellonian University
      • • Department of Medical Biotechnology
      • • Department of Cell Biochemistry
      • • Department of Clinical Biochemistry
      Cracovia, Lesser Poland Voivodeship, Poland
  • 2011
    • Virginia Commonwealth University
      • Division of Cardiology
      Richmond, VA, United States
  • 2006
    • Kyushu University
      Hukuoka, Fukuoka, Japan
  • 2001–2005
    • University of Innsbruck
      • Institute of Biochemistry
      Innsbruck, Tyrol, Austria
    • Medical College of Wisconsin
      • Department of Anesthesiology
      Milwaukee, Wisconsin, United States
  • 2003
    • University of Vienna
      • Department of Surgery
      Wien, Vienna, Austria
  • 1995–2002
    • Collegium Medicum of the Jagiellonian University
      • Chair of Clinical Biochemistry
      Cracovia, Lesser Poland Voivodeship, Poland
  • 1999
    • Stanford University
      • Division of Cardiovascular Medicine
      Palo Alto, California, United States