dc.contributor.author
Nageswaran, Vanasa
dc.date.accessioned
2025-01-02T09:13:48Z
dc.date.available
2025-01-02T09:13:48Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/43024
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-42738
dc.description.abstract
Background/ aims: Growing evidence suggests a critical role of distinct gut microbially produced metabolites in developing cardiometabolic and -vascular diseases. The amino-acid-derived metabolite imidazole propionate (ImP) is increased in patients with pre- and type 2 diabetes. However, its impact on endothelial cell physiology and vascular disease has not been examined so far. Here, the effects of ImP were studied on endothelial cell function and inflammatory activation, as well as on endothelial regeneration after injury and development of atherosclerosis in atheroprone Apoe-/- mice.
Methods/ results: Cell culture experiments, next-generation sequencing, western blotting, and immunostaining were performed to identify the potential underlying mechanism of ImP-mediated effects on primary human aortic endothelial cells (HAECs). Transcriptomic profiling of HAECs revealed altered regulation of several genes involved in angiogenesis in ImP-treated cells. In particular, decreased PI3K/ AKT signaling was found upon pre-treatment of ImP, followed by insulin receptor stimulation with IGF-1, which led to an increase in FOXO1 protein expression as well as nuclear accumulation of FOXO1 in HAECs. Consequently, ImP impaired migratory and angiogenetic properties of endothelial cells assessed by scratch wound healing and Matrigel tube formation assay. Moreover, ImP promoted inflammatory activation of endothelial cells, leading to increased expression of pro-inflammatory cell adhesion molecules (VCAM-1, ICAM-1, and E-selectin) and, finally, to increased adhesion of monocytes under flow conditions. In an in vitro rescue experiment, the ImP-mediated pro-inflammatory phenotype was abrogated by targeted gene silencing of FOXO1 in endothelial cells. Vascular regeneration in vivo was analyzed using a carotid artery injury model (CI) in C57BL/6J mice treated with ImP or vehicle for three weeks via drinking water. Re-endothelialization was determined by Evans blue staining three days post-CI. The results showed that treatment with ImP significantly impaired wound healing compared to control animals. Finally, atherosclerotic plaque formation was analyzed in vivo using apolipoprotein E knockout (Apoe-/-) mice fed a standard chow diet (SCD) or high-fat diet (HFD) and simultaneously treated with vehicle or ImP in drinking water for 6 and 12 weeks. Oil red O staining displayed increased atherosclerotic plaque formation in en face aortic arch and aortic root sections upon ImP treatment. CD68 expression was also enhanced in murine atherosclerotic lesions in response to ImP treatment, indicative of increased macrophage accumulation.
Conclusion: The gut microbially produced metabolite ImP impairs the insulin receptor signaling pathway via PI3K/ AKT/ FOXO1 in endothelial cells, thereby affecting their functional properties such as migration, proliferation and angiogenic capacity. Moreover, ImP promotes inflammatory activation of endothelial cells leading to increased monocyte adhesion. These effects result in impaired vascular healing after injury and increased atherosclerosis in atheroprone Apoe-/- mice.
en
dc.format.extent
III, 105 Seiten
dc.rights.uri
http://www.fu-berlin.de/sites/refubium/rechtliches/Nutzungsbedingungen
dc.subject
Imidazole Propionat
en
dc.subject
endothelial regeneration
en
dc.subject
atherosclerosis
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie::572 Biochemie
dc.title
The impact of gut microbial imidazole propionate on endothelial regeneration and the development of atherosclerosis
dc.contributor.gender
female
dc.contributor.firstReferee
Haghikia, Arash
dc.contributor.furtherReferee
Knaus, Petra
dc.date.accepted
2024-03-21
dc.date.embargoEnd
2025-01-01
dc.identifier.urn
urn:nbn:de:kobv:188-refubium-43024-7
dc.title.translated
Der Einfluss des Darm-Mikrobiom-abhängigen Imidazol Propionats auf die endotheliale Regeneration und die Entwicklung von Atherosklerose
ger
refubium.affiliation
Biologie, Chemie, Pharmazie
dcterms.accessRights.dnb
free
dcterms.accessRights.openaire
open access