Dokument: Regulation des Transkriptionsfaktors Grainyhead-like 3 durch Pflanzeninhaltsstoffe in Endothelzellen
| Titel: | Regulation des Transkriptionsfaktors Grainyhead-like 3 durch Pflanzeninhaltsstoffe in Endothelzellen | |||||||
| Weiterer Titel: | Regulation of the transcription factor Grainyhead-like 3 by plant-derived agents in endothelial cells | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=69460 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20250429-111342-1 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Vierkant, Annika [Autor] | |||||||
| Dateien: |
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| Beitragende: | Altschmied, Joachim [Gutachter] Prof. Dr. Gödecke Axel [Gutachter] | |||||||
| Stichwörter: | Koffein; Curcumin; Seneszenz; Grainyhead-like 3; GRHL3; Endothel | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Kardiovaskuläre Erkrankungen sind die häufigste Todesursache weltweit. Bei deren
Entstehung spielt endotheliale Dysfunktion, die durch eine verminderte NO-Produktion und Migrationsfähigkeit von Endothelzellen (EZ) gekennzeichnet ist, eine wichtige Rolle. Bei der endothelialen Dysfunktion, die mit einer chronischen Entzündung einhergeht, kommt es auch zum Auftreten von Stress-induzierter Seneszenz der EZ. Seneszente Zellen haben einen veränderten Metabolismus und sind in ihrer ursprünglichen Funktion eingeschränkt. Der Pflanzeninhaltsstoff Curcumin wird seit Jahrtausenden in der traditionellen asiatischen Medizin eingesetzt. Zahlreiche Studien zeigen, dass Curcumin die Endothelfunktion verbessert. Kaffeekonsum ist in großen epidemiologischen Studien mit einer reduzierten kardiovaskulären Mortalität assoziiert. Koffein, der Hauptwirkstoff von Kaffee, erhöhte in Studien die NO-Produktion von EZ. Der Transkriptionsfaktor Grainyhead-like 3 (GRHL3) ist essenziell für die Funktion der EZ, indem er die endotheliale NO-Synthase (eNOS) aktiviert und so die NO-Produktion und Migration verstärkt. In dieser Arbeit wurde untersucht, ob Curcumin und/oder Koffein den Transkriptionsfaktor GRHL3 in EZ regulieren. Zudem sollte untersucht werden, ob GRHL3 in Stress-induzierter Seneszenz in EZ reguliert ist und ob Koffein einen Einfluss auf Stress-induzierte Seneszenz in EZ hat. Hierfür wurden humane EZ mit Curcumin oder Koffein für 24 h inkubiert. Sowohl die Behandlung mit Curcumin als auch mit Koffein führte zu einer Zunahme der GRHL3-Menge im Immunoblot verglichen mit den Kontrollen. Die Koffein-Behandlung führte auch zu einer Zunahme der grhl3 Expression in der semiquantitativen real-time PCR. Um Stressinduzierte Seneszenz zu erzeugen, wurden EZ zwei Wochen lang mit H2O2 behandelt. Der Nachweis der Seneszenz-Induktion durch H2O2 wurde durch die Hochregulation von nukleärem p21 und die Herunterregulation von eNOS nachgewiesen. Gleichzeitig zeigte sich ein Verlust der GRHL3-Proteinmenge im Immunoblot. Bei gleichzeitiger Behandlung mit Koffein wurde weder die p21 Proteinmengen hochreguliert, noch kam es zu einer Veränderung von GRHL3 und eNOS im Vergleich zur Kontrolle. Aus den Ergebnissen lässt sich folgern: Erstens regulieren Curcumin und Koffein den vasoprotektiven Transkriptionsfaktor GRHL3 in EZ hoch. Zweitens ist GRHL3 in Stress-induzierter Seneszenz herunterreguliert. Drittens verhindert Koffein Stress-induzierte Seneszenz in EZ durch Erhaltung der Proteinmengen von GRHL3 und eNOS. Die Pflanzeninhaltsstoffe Curcumin und Koffein könnten langfristig neue Optionen in der Prävention und Therapie von kardiovaskulären Erkrankungen darstellen.Cardiovascular diseases (CVDs) are the leading cause of death across the globe. Endothelial dysfunction, which is characterized by reduced NO production and migratory capacity of endothelial cells (EC), plays an important role in their development. Endothelial dysfunction, that goes along with chronic inflammation, also encompasses the occurrence of stress-induced senescence of EC. Senescent cells have an altered metabolism and are impaired in their original functions. The plant compound curcumin has been used in traditional Asian medicine for thousands of years. In many studies curcumin has been shown to improve endothelial function. Coffee consumption has been associated with reduced cardiovascular mortality in large epidemiological studies. Studies have shown that caffeine, the main active ingredient in coffee, increases NO production of EC. The transcription factor Grainyhead-like 3 (GRHL3) is essential for EC function as it activates endothelial NO synthase (eNOS), thereby enhancing NO production and migration. In this study it was investigated whether curcumin and/or caffeine regulate the transcription factor GRHL3 in EC. In addition, it was investigated if GRHL3 is regulated in stress-induced senescence in EC and if caffeine has an influence on stress-induced endothelial cell senescence. Therefore, human EC were incubated for 24 h with curcumin or caffeine, respectively. Curcumin and caffeine treatment both lead to an increase of GRHL3 protein level compared to controls in immunoblot analysis. Caffeine treatment also led to an increase of grhl3 expression in semiquantitative real-time PCR. To induce stress-induced senescence, EC were treated with H2O2 for two weeks. Senescence induction by H2O2 was proven by upregulation of nuclear p21 and downregulation of eNOS. Concomitantly, GRHL3 protein levels were reduced as shown by immunoblot. Simultaneous treatment with caffeine did not lead to upregulation of p21 protein levels compared to controls, and, moreover, GRHL3 and eNOS protein levels were unaltered. From these results the following conclusions can be drawn: Firstly, curcumin and caffeine both upregulate the vasoprotective transcription factor GRHL3 in EC. Secondly, GRHL3 is downregulated in stress-induced EC senescence. Thirdly, caffeine prevents stress-induced senescence in EC by sustaining GRHL3 and eNOS protein levels. In the long run, the plant compounds curcumin and caffeine could therefore offer new options in the prevention and therapy of CVDs. | |||||||
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| Rechtliche Vermerke: | Teile dieser Arbeit wurden veröffentlicht:
Cox, F.F.*, Misiou, A.*, Vierkant, A., Ale-Agha, N., Grandoch, M., Haendeler, J., Altschmied, J., (2022), Protective Effects of Curcumin in Cardiovascular Diseases-Impact on Oxidative Stress and Mitochondria. Cells, (11, 3), 342. Merk, D.*, Greulich, J.*, Vierkant, A., Cox, F., Eckermann, O., von Ameln, F., Dyballa-Rukes, N., Altschmied, J., Ale-Agha, N., Jakobs, P., Haendeler, J., (2023), Caffeine Inhibits Oxidative Stress- and Low Dose Endotoxemia-Induced Senescence-Role of Thioredoxin-1, Antioxidants (12, 6), 1244. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 29.04.2025 | |||||||
| Dateien geändert am: | 29.04.2025 | |||||||
| Promotionsantrag am: | 02.12.2024 | |||||||
| Datum der Promotion: | 10.04.2025 |
