The antiatherosclerotic action of 1G244 – An inhibitor of dipeptidyl peptidases 8/9 – is mediated by the induction of macrophage death

Abstract

BackgroundTargeting cell death to induce favorable functional and morphological changes within atherosclerotic plaques has long been postulated as a promising anti-atherosclerotic strategy. In this regard, inhibition of dipeptidyl peptidases 8/9 has received special attention in the context of chronic inflammatory diseases due to its regulatory role in macrophage death in vivo. MethodsThe present study investigates the influence of prolonged treatment with 1G244 – an inhibitor of dipeptidyl peptidases 8/9 – on the development of the advanced atherosclerosis plaque in apoE-knockout mice, using morphometric and molecular methods. Results1G244 administration has led to a reduction in atherosclerotic plaque size in an apoE-knockout mice model. Moreover, it reduced the content of in-plaque macrophages, attributed by immunohistochemical phenotyping to the pro-inflammatory M1-like activation state of these cells. Inhibition of dipeptidyl peptidases 8/9 augmented the lytic form of death response of activated macrophages in-vitro. ConclusionsIn summary, inhibition of DPP 8/9 elicited an anti-atherosclerotic effect in apoE−/− mice, which can be attributed to the lytic form of death induction in activated macrophages, as assessed by the in vitro BMDM model. This, in turn, results in a reduction of the plaque area without its transformation towards a rupture-prone morphology.