5-Methoxyleoligin, a Lignan from Edelweiss, Stimulates CYP26B1-Dependent Angiogenesis In Vitro and Induces Arteriogenesis in Infarcted Rat Hearts In Vivo
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{"title"=>"5-Methoxyleoligin, a Lignan from Edelweiss, Stimulates CYP26B1-Dependent Angiogenesis In Vitro and Induces Arteriogenesis in Infarcted Rat Hearts In Vivo", "type"=>"journal", "authors"=>[{"first_name"=>"Barbara", "last_name"=>"Messner", "scopus_author_id"=>"7003427439"}, {"first_name"=>"Johann", "last_name"=>"Kern", "scopus_author_id"=>"23570576000"}, {"first_name"=>"Dominik", "last_name"=>"Wiedemann", "scopus_author_id"=>"26639916000"}, {"first_name"=>"Stefan", "last_name"=>"Schwaiger", "scopus_author_id"=>"6602746607"}, {"first_name"=>"Adrian", "last_name"=>"Türkcan", "scopus_author_id"=>"54685491000"}, {"first_name"=>"Christian", "last_name"=>"Ploner", "scopus_author_id"=>"36776543400"}, {"first_name"=>"Alexander", "last_name"=>"Trockenbacher", "scopus_author_id"=>"6506515647"}, {"first_name"=>"Klaus", "last_name"=>"Aumayr", "scopus_author_id"=>"6506502082"}, {"first_name"=>"Nikolaos", "last_name"=>"Bonaros", "scopus_author_id"=>"6602270254"}, {"first_name"=>"Günther", "last_name"=>"Laufer", "scopus_author_id"=>"7102956369"}, {"first_name"=>"Hermann", "last_name"=>"Stuppner", "scopus_author_id"=>"56212005200"}, {"first_name"=>"Gerold", "last_name"=>"Untergasser", "scopus_author_id"=>"6603610205"}, {"first_name"=>"David", "last_name"=>"Bernhard", "scopus_author_id"=>"7004460543"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "sgr"=>"84874873449", "pui"=>"368517978", "pmid"=>"23554885", "issn"=>"19326203", "scopus"=>"2-s2.0-84874873449", "doi"=>"10.1371/journal.pone.0058342"}, "id"=>"0397ca0a-e376-37fc-8d09-061230100296", "abstract"=>"BACKGROUND: Insufficient angiogenesis and arteriogenesis in cardiac tissue after myocardial infarction (MI) is a significant factor hampering the functional recovery of the heart. To overcome this problem we screened for compounds capable of stimulating angiogenesis, and herein investigate the most active molecule, 5-Methoxyleoligin (5ML), in detail. METHODS AND RESULTS: 5ML potently stimulated endothelial tube formation, angiogenic sprouting, and angiogenesis in a chicken chorioallantoic membrane assay. Further, microarray- and knock down- based analyses revealed that 5ML induces angiogenesis by upregulation of CYP26B1. In an in vivo rat MI model 5ML potently increased the number of arterioles in the peri-infarction and infarction area, reduced myocardial muscle loss, and led to a significant increase in LV function (plus 21% 28 days after MI). CONCLUSION: The present study shows that 5ML induces CYP26B1-dependent angiogenesis in vitro, and arteriogenesis in vivo. Whether or not CYP26B1 is relevant for in vivo arteriogenesis is not clear at the moment. Importantly, 5ML-induced arteriogenesis in vivo makes the compound even more interesting for a post MI therapy. 5ML may constitute the first low molecular weight compound leading to an improvement of myocardial function after MI.", "link"=>"http://www.mendeley.com/research/5methoxyleoligin-lignan-edelweiss-stimulates-cyp26b1dependent-angiogenesis-vitro-induces-arteriogene", "reader_count"=>7, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Student > Doctoral Student"=>2, "Student > Master"=>1, "Lecturer"=>2, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Student > Doctoral Student"=>2, "Student > Master"=>1, "Lecturer"=>2, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Medicine and Dentistry"=>4, "Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/985461"], "description"=>"<p><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g002\" target=\"_blank\">Figure 2A:</a> CAMs of 3-days- old chickens were incubated for 96 hours with the control solution (DMSO as the solvent control) or 0.1 or 0.5 µg 5ML. <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g002\" target=\"_blank\">Figure 2A</a> shows that the treatment with 5ML enhanced the formation of new blood vessels. 5ML significantly increased blood vessel formation at a concentration of 0.5 µg/egg. <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g002\" target=\"_blank\">Figure 2B</a> shows representative images of the CAM-assay (Magnification: 12,5×). Blood vessels were counted in the ring area of the CAM to quantify effects of 5ML <i>in vivo</i>. All experiments were performed in triplicates. Asterisks indicate significant differences (* p<0.05) compared to the corresponding controls.</p>", "links"=>[], "tags"=>["5ml", "chorioallantoic", "membrane", "assay"], "article_id"=>650779, "categories"=>["Physiology"], "users"=>["Barbara Messner", "Johann Kern", "Dominik Wiedemann", "Stefan Schwaiger", "Adrian Türkcan", "Christian Ploner", "Alexander Trockenbacher", "Klaus Aumayr", "Nikolaos Bonaros", "Günther Laufer", "Hermann Stuppner", "Gerold Untergasser", "David Bernhard"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058342.g002", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_5ML_on_blood_vessel_formation_in_the_chicken_chorioallantoic_membrane_assay_CAM_assay_/650779", "title"=>"Effects of 5ML on blood vessel formation in the chicken chorioallantoic membrane assay (CAM) assay.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-13 10:03:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/985479"], "description"=>"<p><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g006\" target=\"_blank\">Figure 6A</a> shows the quantification of the capillary density in the infarction and peri-infarction area on HE stained heart sections (n = 7 per group). Representative images of capillaries in the infraction area are shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g006\" target=\"_blank\">Figure 6B</a> (black arrows; magnification 100×). Quantitative image analysis of the arteriole density in the peri-infarction and infarction area of all animals (n = 7 per group) are shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g006\" target=\"_blank\">Figure 6C</a> and representative images of arterioles in the infarction area are shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g006\" target=\"_blank\">Figure 6D</a> (black arrows; magnification 63×). The effect of 5ML in an <i>in vitro</i> wound scratch assay with HUVECs and SMCs is depicted in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g006\" target=\"_blank\">Figure 6E</a> (data are expressed as% scratch closure after 6 hours). The in vitro experiments were performed in triplicates. Asterisks indicate significant differences (* p<0.05; ** p<0.01) compared to the corresponding controls or control group.</p>", "links"=>[], "tags"=>["arteriogenesis", "peri-infarction", "infarction", "hearts", "mi", "activates", "cells", "endothelial"], "article_id"=>650792, "categories"=>["Physiology"], "users"=>["Barbara Messner", "Johann Kern", "Dominik Wiedemann", "Stefan Schwaiger", "Adrian Türkcan", "Christian Ploner", "Alexander Trockenbacher", "Klaus Aumayr", "Nikolaos Bonaros", "Günther Laufer", "Hermann Stuppner", "Gerold Untergasser", "David Bernhard"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058342.g006", "stats"=>{"downloads"=>3, "page_views"=>38, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_5ML_treatment_induces_arteriogenesis_in_the_peri_infarction_and_infarction_area_of_rat_hearts_after_MI_and_activates_the_migration_ability_of_smooth_muscle_cells_as_well_as_endothelial_cells_/650792", "title"=>"5ML treatment induces arteriogenesis in the peri-infarction and infarction area of rat hearts after MI and activates the migration ability of smooth muscle cells as well as endothelial cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-13 10:07:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/985477"], "description"=>"<p><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g005\" target=\"_blank\">Figure 5A</a> shows the quantification of the viable cardiac tissue within the highly fibrotic infarction area (n = 7 per group). <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g005\" target=\"_blank\">Figure 5B</a> shows the staining of heart sections with Masson's Trichrome that visualizes the viable heart muscle (red staining) and the fibrotic area (intensive blue staining) (magnification 63×). Quantitative image analysis (of all images, n = 7 per group) of the CYP26B1 expression in the infarction area is depicted in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g005\" target=\"_blank\">Figure 5C</a>. <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g005\" target=\"_blank\">Figure 5D</a> shows representative images of CYP26B1-immunohistochemically stained heart sections of control and 5ML treated rat hearts (magnification 100×). Quantification of the number of Tunel positive nuclei in the peri-infarction area is shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g005\" target=\"_blank\">Figure 5E</a> (n = 7 per group). <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g005\" target=\"_blank\">Figure 5F</a> shows representative images of Tunel-stained cardiomyocytes in the per-infarction area of control and 5ML treated rat hearts (magnification 40×). Asterisks indicate significant differences (* p<0.05; ** p<0.01) compared to the corresponding control group.</p>", "links"=>[], "tags"=>["viable", "cardiac", "cyp26b1", "infarction", "tunel", "cells", "peri-infarction"], "article_id"=>650790, "categories"=>["Physiology"], "users"=>["Barbara Messner", "Johann Kern", "Dominik Wiedemann", "Stefan Schwaiger", "Adrian Türkcan", "Christian Ploner", "Alexander Trockenbacher", "Klaus Aumayr", "Nikolaos Bonaros", "Günther Laufer", "Hermann Stuppner", "Gerold Untergasser", "David Bernhard"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058342.g005", "stats"=>{"downloads"=>1, "page_views"=>31, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_5ML_treatment_increase_the_amount_of_viable_cardiac_tissue_increases_the_CYP26B1_expression_in_the_infarction_area_and_reduces_the_number_of_Tunel_positive_cells_in_the_peri_infarction_area_/650790", "title"=>"5ML treatment increase the amount of viable cardiac tissue, increases the CYP26B1 expression in the infarction area, and reduces the number of Tunel positive cells in the peri-infarction area.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-13 10:06:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/985482"], "description"=>"<div><p>Background</p><p>Insufficient angiogenesis and arteriogenesis in cardiac tissue after myocardial infarction (MI) is a significant factor hampering the functional recovery of the heart. To overcome this problem we screened for compounds capable of stimulating angiogenesis, and herein investigate the most active molecule, 5-Methoxyleoligin (5ML), in detail.</p> <p>Methods and Results</p><p>5ML potently stimulated endothelial tube formation, angiogenic sprouting, and angiogenesis in a chicken chorioallantoic membrane assay. Further, microarray- and knock down- based analyses revealed that 5ML induces angiogenesis by upregulation of CYP26B1. In an <i>in vivo</i> rat MI model 5ML potently increased the number of arterioles in the peri-infarction and infarction area, reduced myocardial muscle loss, and led to a significant increase in LV function (plus 21% 28 days after MI).</p> <p>Conclusion</p><p>The present study shows that 5ML induces CYP26B1-dependent angiogenesis <i>in vitro</i>, and arteriogenesis <i>in vivo</i>. Whether or not CYP26B1 is relevant for <i>in vivo</i> arteriogenesis is not clear at the moment. Importantly, 5ML-induced arteriogenesis <i>in vivo</i> makes the compound even more interesting for a post MI therapy. 5ML may constitute the first low molecular weight compound leading to an improvement of myocardial function after MI.</p> </div>", "links"=>[], "tags"=>["lignan", "stimulates", "cyp26b1-dependent", "angiogenesis", "vitro", "arteriogenesis", "infarcted", "hearts", "vivo"], "article_id"=>650795, "categories"=>["Physiology"], "users"=>["Barbara Messner", "Johann Kern", "Dominik Wiedemann", "Stefan Schwaiger", "Adrian Türkcan", "Christian Ploner", "Alexander Trockenbacher", "Klaus Aumayr", "Nikolaos Bonaros", "Günther Laufer", "Hermann Stuppner", "Gerold Untergasser", "David Bernhard"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058342", "stats"=>{"downloads"=>7, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/5_Methoxyleoligin_a_Lignan_from_Edelweiss_Stimulates_CYP26B1_Dependent_Angiogenesis_In_Vitro_and_Induces_Arteriogenesis_in_Infarcted_Rat_Hearts_In_Vivo__/650795", "title"=>"5-Methoxyleoligin, a Lignan from Edelweiss, Stimulates CYP26B1-Dependent Angiogenesis In Vitro and Induces Arteriogenesis in Infarcted Rat Hearts In Vivo", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-03-13 10:07:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/985467"], "description"=>"<p><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g003\" target=\"_blank\">Figures 3A and 3B</a> show median values +/− S.D. of microarray-based analyses of gene-regulation by 5ML in relation to controls 6 and 24 hours after the addition of 5ML (10 µM). <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g003\" target=\"_blank\">Figure 3C</a> shows that despite the fact that the knockdown of CYP1A1 had a significant inhibitory effect on spontaneous angiogenesis in HUVECs; CYP1A1 knockdown had no effect on angiogenesis increased by 5ML. Similarly, CYP26B1 knockdown potently repressed spontaneous angiogenesis in HUVECS and in addition completely abrogated 5ML-induced tube formation. Shown are mean values of two independent experiments performed in triplicates +/− SD. * p<0.05. <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g003\" target=\"_blank\">Figure 3D</a> shows Western blot analyses of effects of the CYP1A1- and the CYP26B1-specific knockdown on protein expression of the corresponding proteins. Asterisks indicate significant differences (* p<0.05) compared to the corresponding controls.</p>", "links"=>[], "tags"=>["alters", "transcription", "cyp26b1", "causal", "mediator", "5ml", "-induced"], "article_id"=>650780, "categories"=>["Physiology"], "users"=>["Barbara Messner", "Johann Kern", "Dominik Wiedemann", "Stefan Schwaiger", "Adrian Türkcan", "Christian Ploner", "Alexander Trockenbacher", "Klaus Aumayr", "Nikolaos Bonaros", "Günther Laufer", "Hermann Stuppner", "Gerold Untergasser", "David Bernhard"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058342.g003", "stats"=>{"downloads"=>3, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_5ML_alters_the_transcription_of_a_small_set_of_genes_CYP26B1_is_the_causal_mediator_of_5ML_induced_angiogenesis_/650780", "title"=>"5ML alters the transcription of a small set of genes; CYP26B1 is the causal mediator of 5ML -induced angiogenesis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-13 10:04:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/985460"], "description"=>"<p><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g001\" target=\"_blank\">Figure 1A:</a> Effects of increasing concentrations of 5ML on human endothelial cells were analyzed in a capillary tube formation assay in matrigel (magnification: 100×). <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g001\" target=\"_blank\">Figure 1B:</a> Numbers of capillaries per mm<sup>2</sup> were determined 6 hours after incubation with 1 and 10 µM 5ML. <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g001\" target=\"_blank\">Figure 1C:</a> Spheroids of HUVECs were stimulated with 50 ng/mL VEGF and different concentrations of 5ML or DMSO as solvent control. Cumulative sprout length (CSL) was analyzed 24 hours after stimulation (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g001\" target=\"_blank\">Figure 1D</a>). All experiments were performed in triplicates. Asterisks indicate significant differences (* p<0.05) compared to the corresponding controls.</p>", "links"=>[], "tags"=>["capillary", "angiogenic", "sprouting", "endothelial", "cells"], "article_id"=>650777, "categories"=>["Physiology"], "users"=>["Barbara Messner", "Johann Kern", "Dominik Wiedemann", "Stefan Schwaiger", "Adrian Türkcan", "Christian Ploner", "Alexander Trockenbacher", "Klaus Aumayr", "Nikolaos Bonaros", "Günther Laufer", "Hermann Stuppner", "Gerold Untergasser", "David Bernhard"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058342.g001", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_5ML_promotes_capillary_tube_formation_and_angiogenic_sprouting_of_human_endothelial_cells_in_a_dose_dependent_manner_/650777", "title"=>"5ML promotes capillary tube formation and angiogenic sprouting of human endothelial cells in a dose dependent manner.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-13 10:03:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/985475"], "description"=>"<p><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g004\" target=\"_blank\">Figure 4A</a> shows data from an ultrasound-based analysis of the LV ejection fraction in rats before (baseline) and after MI (day 1, 14 and 28 post MI), either after the injection of the solvent control or the injection of 5ML. Shown are mean values +/− SD of all animals (n = 7 per group). <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g004\" target=\"_blank\">Figure 4B</a> shows the quantitative analysis of the infarction size (shown as% of total heart size) of control and 5ML treated rat hearts (n = 7 per group). The septum diameter of control and 5ML treated (n = 7 per group) rat hearts was analyzed and results are depicted in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g004\" target=\"_blank\">Figure 4C</a>. Representative images of Masson Trichrome stained control and 5ML treated heart sections are shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0058342#pone-0058342-g004\" target=\"_blank\">Figure 4D</a> (magnification 20×). Asterisks indicate significant differences (* p<0.05; *** p<0.001) compared to the corresponding control group.</p>", "links"=>[], "tags"=>["improves", "ejection", "inhibits", "cardiac", "infarction", "rats"], "article_id"=>650788, "categories"=>["Physiology"], "users"=>["Barbara Messner", "Johann Kern", "Dominik Wiedemann", "Stefan Schwaiger", "Adrian Türkcan", "Christian Ploner", "Alexander Trockenbacher", "Klaus Aumayr", "Nikolaos Bonaros", "Günther Laufer", "Hermann Stuppner", "Gerold Untergasser", "David Bernhard"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0058342.g004", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_5ML_treatment_improves_the_ejection_fraction_inhibits_cardiac_hypertrophy_but_has_no_effect_on_the_infarction_size_in_rats_after_MI_/650788", "title"=>"5ML treatment improves the ejection fraction, inhibits cardiac hypertrophy, but has no effect on the infarction size in rats after MI.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-13 10:04:55"}

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Relative Metric

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