Inhibition of CD40-TRAF6 signaling protects against aneurysm development and progression

Ommer-Blaesius, M.; Vajen, T.; Elster, C.; Verheyen, S.; Pfeiler, S.; Quast, C.; Odendahl, J.; Lang, A.; Lutgens, E.; Kelm, M.; Gerdes, N.

doi:10.1101/2023.03.24.534110

bioRxiv · 10.1101/2023.03.24.534110

Inhibition of CD40-TRAF6 signaling protects against aneurysm development and progression

Ommer-Blaesius, M.·Vajen, T.·Elster, C.·Verheyen, S.·Pfeiler, S.·Quast, C.·Odendahl, J.·Lang, A.·Lutgens, E.·Kelm, M.·Gerdes, N.

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Abstract

ObjectiveInflammation is a critical process during the progressive development and complication of abdominal aortic aneurysm. The co-stimulatory dyad CD40-CD40L is a major driver of inflammation and modulates immune responses. This study evaluates the potential of a small molecule inhibitor, which blocks the interaction between CD40 and tumor necrosis factor (TNF) receptor-associated factor (TRAF)-6, referred to as TRAF-STOP, in the early and later phase during AAA progression. Methods and resultsAAAs were induced in C57BL/6J mice by infrarenal aortic porcine pancreatic elastase infusion for 7, 14 or 28 days. Inhibition of CD40 signaling by TRAF-STOP resulted in less severe AAA formation and reduced the incidence of AAA development. TRAF-STOP treatment attenuated aortic structural remodeling, characterized by a reduced elastic fiber degradation, lowered expression of matrix metalloproteinase (MMP)-2 and MMP9, as well as preserved collagen type IV content in aneurysmal tissue. Furthermore, this is accompanied by the reduction of key pro-inflammatory genes such as TNF. ConclusionPharmacological inhibition of CD40-TRAF6 signaling protects from adverse aortic structural remodeling during the early phase of AAA progression representing a translational strategy to limit progression of human AAA disease.

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Ommer-Blaesius, M., Vajen, T., Elster, C., Verheyen, S., Pfeiler, S., Quast, C., Odendahl, J., Lang, A., Lutgens, E., Kelm, M., Gerdes, N.. 2023-03-25. Inhibition of CD40-TRAF6 signaling protects against aneurysm development and progression. https://doi.org/10.1101/2023.03.24.534110

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