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

Background: Targeting cell death to induce favorable functional and morphological changes within atheroscle-rotic 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. Methods: The 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. Results: 1G244 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 phe-notyping 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. Conclusions: In 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.

Automated summary

Inhibition of dipeptidyl peptidases 8/9 induces lytic cell death in activated macrophages, leading to a reduction in atherosclerotic plaque size.