Dokument: Untersuchungen zum Mechanismus des IGF1-induzierten kardialen Funktionserhalts nach akutem Myokardinfarkt
| Titel: | Untersuchungen zum Mechanismus des IGF1-induzierten kardialen Funktionserhalts nach akutem Myokardinfarkt | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=69054 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20250422-112542-3 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Boy, Johannes Alexander Tobias [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Gödecke, Axel [Gutachter] Prof. Dr. Jung, Christian [Gutachter] Dr. Temme, Sebastian [Gutachter] | |||||||
| Stichwörter: | Myokardinfarkt, IGF1, kardiales Remodeling | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Im Jahr 2021 stellte die chronische ischämische Herzkrankheit in Deutschland mit circa 74.500 Sterbefällen die häufigste Todesursache dar, wobei etwa 45.000 Patienten an einem akuten Herzinfarkt verstarben. Infolge zahlreicher moderner Interventionstherapien und einer seit Jahren rückläufigen Mortalität nach einem akutem Myokardinfarkt entwickeln viele der Patienten, welche einen akuten Myokardinfarkt überleben, eine Herzinsuffizienz.
Der insulin-ähnliche Wachstumsfaktor 1 (IGF-1) scheint einen wichtigen Einfluss auf den Krankheitsverlauf nach einem Myokardinfarkt zu nehmen. So ist das Risiko, an einer ischämischen Herzerkrankung zu erkranken, bei einem niedrigen IGF-1-Serumspiegel erhöht. Zudem gibt es Hinweise darauf, dass IGF-1 kardioprotektiv wirkt und die kardiale Remodellierung nach einem Myokardinfarkt positiv beeinflusst. Unsere Arbeitsgruppe konnte in einem Mausmodell nachweisen, dass eine IGF-1-Gabe in der Reperfusion zu einem Erhalt der kardialen Pumpfunktion, einer reduzierten Narbengröße sowie einer gesteigerten Vaskularisierung eine Woche nach dem Myokardinfarkt führt. Dabei sind die molekularen und gewebsmorphologischen Wirkmechanismen infolge einer IGF-1-Gabe in der Frühphase noch nicht ausreichend verstanden. Ziel dieser Arbeit war es daher, die frühen Effekte einer IGF-1-Kurzzeittherapie auf Zellproliferation, Angiogenese, Entzündungsreaktion sowie auf die Genexpression innerhalb der ersten Woche nach einem Myokardinfarkt im Tiermodell zu untersuchen. Hierfür wurde an Mäusen mittels einer Koronararterienligatur ein 45-minütiger Myokardinfarkt mit Reperfusion initiiert. Die Tiere der Interventionsgruppe erhielten IGF-1 (40 ng/g Bolus sowie 1 μg/g/d über 3 Tage). Die Herzen wurden nach 2, 3 oder 5 Tagen entnommen und immunhistochemisch gefärbt. Die histologisch-morphometrischen Auswertungen zeigten zu den verschiedenen Zeitpunkten keine Unterschiede bezüglich der Zahl a) aller Zellen (DAPI), b) proliferierender Zellen (EdU) und c) Endothelzellen (CD31). Dabei erfolgte eine separate Auswertung der Regionen (1) Risikogebiet („area at risk“, AAR), (2) Randzone und (3) nicht-infarziertes Myokard (niM). Die IGF-1-induzierten Effekte auf die Proliferation und Migration von Endothelzellen wurden im Rahmen eines translationalen Ansatzes mittels eines HUVEC-Zell-Migrationsassays in Zellkultur untersucht. Bei HUVEC-Zellen führte eine IGF-1-Gabe hinsichtlich des Migrationsverhaltens und der Proliferation zu keiner Änderung im Vergleich zur Kontrollmedium-Gabe. Auch nach Behandlung mit Makrophagenserum von IGF-1-behandelten Makrophagen änderten sich die Parameter nicht. Zur Untersuchung der IGF-1-bezogenen Immunantwort wurden Makrophagen (CD68) 5 Tage nach Myokardinfarkt immunhistochemisch gefärbt. Hierbei konnten in den verschiedenen Regionen keine Effekte einer IGF-1 Behandlung auf die Gesamtzahl der Makrophagen sowie auf die Makrophagen-Proliferation nachgewiesen werden. Um auf molekularer Ebene Erkenntnisse über die dem IGF-1-Effekt zugrunde liegenden Mechanismen zu gewinnen, wurden Microarray-basiert kanonische Pathwayanalysen der Genexpression von Herzgewebe, welches 1, 2 oder 7 Tage nach Infarkt gewonnen wurde (AAR und niM), durchgeführt. Bei IGF-1-behandelten Mäusen zeigte sich in der AAR (Tag 1,2) eine abgeschwächte Aktivierung verschiedener Signalwege der Entzündungsreaktion, etwa bei der „Leukozytenmigration“, der „Aktivierung der Leukozyten“, oder der „Aktivierung myeloider Zellen“ gegenüber niM (Tag 7). Diese Effekte zeigten sich am deutlichsten an Tag eins nach Myokardinfarkt, nahmen an Tag zwei ab und waren an Tag sieben nicht mehr nachweisbar. Schlussfolgerung: Eine IGF-1-Gabe nach einem Myokardinfarkt führt zu einer ausgeprägten Modulation der Expression von Genen, welche mit Entzündungsprozessen assoziiert sind. Da IGF-1 zu den Zeitpunkten 2, 3 und 5 Tage nach Infarkt keinen Effekt hinsichtlich angiogenetischer Prozesse hatte, erscheint es wahrscheinlich, dass diese erst zu einem späteren Zeitpunkt histologisch erfassbar in Erscheinung treten. Bei konstanter Makrophagenzahl nach IGF-1-Gabe 5 Tage nach Infarkt werden anstelle regional quantitativer Veränderungen qualitative Unterschiede des Makrophagenphänotyps vermutet. Weder die alleinige Gabe von IGF-1 noch die Gabe von Makrophagenserum IGF-1 behandelter Makrophagen führen zu einer Steigerung der Proliferationsrate und Migration humaner Endothelzellen, womit in vivo komplexere Wirkmechanismen zur Neovaskularisierung angenommen werden.In 2021, chronic ischemic heart disease was the most common cause of death in Germany, with approximately 74,500 deaths, while 45,000 patients died from acute myocardial infarction. Despite numerous modern intervention therapies and a decrease in mortality after acute myocardial infarction, many of the patients who survive AMI develop heart failure. Insulin-like growth factor 1 (IGF-1) appears to have an important influence on disease progression after myocardial infarction. IGF-1 significantly modulates disease progression after AMI. Low serum concentrations of IGF-1 increase the risk of ischemic heart disease. There is also evidence that IGF-1 has a cardioprotective effect and positively influences cardiac remodeling after myocardial infarction. In earlier studies, our research group demonstrated in a mouse model that IGF-1 administration starting with reperfusion leads to preservation of cardiac pump function, reduced scar size, and increased vascularization one week after myocardial infarction. The molecular and histological mechanisms of action resulting from IGF-1 administration in the early phase after myocardial infarction are poorly understood. The aim of this project was to investigate the early effects of IGF-1 short-term therapy in an animal model on cell proliferation, angiogenesis, inflammatory response, and gene expression within the first week after myocardial infarction. For this purpose, we induced a 45-minute myocardial infarction with reperfusion via temporary ligation of the coronary artery in C57BL/6J mice. Animals in the intervention group received IGF-1 (40 ng/g bolus and 1 μg/g/d for 3 days). Hearts were harvested after 2, 3, or 5 days and immunohistochemically stained. A separate evaluation of the regions (1) area-at-risk (AAR), (2) border zone, and (3) non-infarcted myocardium (niM) was performed. Histology did not show differences in the number of a) all cells (DAPI), b) proliferating cells (5’-Ethynyl-2′-deoxyuridine, EdU), and c) endothelial cells (CD31) at the examined time points. To investigate the IGF-1-related immune response, hearts were immunostained for macrophages (CD68) 5 days after myocardial infarction. As a result, IGF-1 treatment did not change the total number of macrophages or macrophage proliferation in the different regions. Another objective of this study was to explore how IGF-1 short-term therapy affects early cardiac gene expression following myocardial infarction. Therefore, we performed a spatial microarray-based canonical pathway analysis at different time points after AMI. To initiate a myocardial infarction, we used the mouse model with infarction/reperfusion as described above. After infarction, animals in the intervention group received IGF-1 (40 ng/g bolus and 1 μg/g/d for 3 days), and hearts were harvested 1, 2, or 7 days after infarction. AAR of IGF-1-treated and untreated mice on day 1, 2, and 7 was compared to niM on day 7 after infarction. IGF-1-treated mice showed attenuated activation of various signaling pathways of the inflammatory response, such as "leukocyte migration", "leukocyte activation", or "myeloid cell activation". These effects were most evident on day 1 after myocardial infarction, decreased on day 2, and were no longer detectable on day 7. Thus, it is likely that IGF-1 shows its underlying effects through an altered activation of immune cells. Conclusion: The administration of IGF-1 following a myocardial infarction leads to a significant alteration in the expression of genes associated with inflammatory processes. As IGF-1 had no effect on angiogenic processes at the time points of 2, 3, and 5 days post-infarction, it is probable that histological detection of these effects will occur later. With constant macrophage numbers after IGF-1 administration 5 days after infarction, qualitative differences in macrophage phenotype are suspected instead of regional quantitative changes. Neither the administration of IGF-1 nor the application of serum from macrophages treated with IGF-1 led to an increase in the proliferation rate and migration of human endothelial cells, suggesting more complex mechanisms of action for neovascularization in vivo. | |||||||
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Acute myocardial infarction activates distinct inflammation and proliferation pathways in circulating monocytes, prior to recruitment, and identified through conserved transcriptional responses in mice and humans. European heart journal. 2015;36(29):1923-34. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Bezug: | 2018-2025 | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät » Institute » Institut für Herz- und Kreislaufphysiologie | |||||||
| Dokument erstellt am: | 22.04.2025 | |||||||
| Dateien geändert am: | 22.04.2025 | |||||||
| Promotionsantrag am: | 08.06.2024 | |||||||
| Datum der Promotion: | 13.02.2025 |
