Immunoproteasomal inhibition with ONX-0914 attenuates atherosclerosis and reduces white adipose tissue mass and metabolic syndrome in mice

Schaftenaar, F.H.; Dam, A.D. van; Bruin, G. de; Depuydt, M.A.C.; Mol, J.; Amersfoort, J.; ... ; Kuiper, J. (2024)

Article / Letter to editor

Atherosclerosis is the major underlying pathology of cardiovascular disease and is driven by dyslipidemia and inflammation. Inhibition of the immunoproteasome, a proteasome variant that is predominantly expressed by immune cells and plays an important role in antigen presentation, has been shown to have immunosuppressive effects.

We assessed the effect of ONX-0914, an inhibitor of the immunoproteasomal catalytic subunits LMP7 (proteasome subunit β5i/large multifunctional peptidase 7) and LMP2 (proteasome subunit β1i/large multifunctional peptidase 2), on atherosclerosis and metabolism in LDLr^-/- and APOE*3-Leiden.CETP mice.

ONX-0914 treatment significantly reduced atherosclerosis, reduced dendritic cell and macrophage levels and their activation, as well as the levels of antigen-experienced T cells during early plaque formation, and Th1 cells in advanced atherosclerosis in young and aged mice in various immune compartments. Additionally, ONX-0914 treatment led to a strong reduction in white adipose tissue mass and adipocyte progenitors, which coincided with neutrophil and macrophage accumulation in white adipose tissue. ONX-0914 reduced intestinal triglyceride uptake and gastric emptying, likely contributing to the reduction in white adipose tissue mass, as ONX-0914 did not increase energy expenditure or reduce total food intake. Concomitant with the reduction in white adipose tissue mass upon ONX-0914 treatment, we observed improvements in markers of metabolic syndrome, including lowered plasma triglyceride levels, insulin levels, and fasting blood glucose.

We propose that immunoproteasomal inhibition reduces 3 major causes underlying cardiovascular disease, dyslipidemia, metabolic syndrome, and inflammation and is a new target in drug development for atherosclerosis treatment.

• All authors: Schaftenaar, F.H.; Dam, A.D. van; Bruin, G. de; Depuydt, M.A.C.; Mol, J.; Amersfoort, J.; Douna, H.; Meijer, M.; Kröner, M.J.; Santbrink, P.J. van; Bernabé Kleijn, M.N.A.; Puijvelde, G.H.M. van; Florea, B.I.; Slütter, B.; Foks, A.C.; Bot, I.; Rensen, P.C.N.; Kuiper, J.
• Date: 2024-04-25
• Journal: Arteriosclerosis, Thrombosis, and Vascular Biology
• Volume: 44
• Issue: 6
• DOI: doi:10.1161/ATVBAHA.123.319701
• Link: https://www.ahajournals.org/doi/10.1161/ATVBAHA.123.319701