Immunoproteasomal Inhibition With ONX-0914 Attenuates Atherosclerosis and Reduces White Adipose Tissue Mass and Metabolic Syndrome in Mice.

Autor:	Schaftenaar FH; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, the Netherlands (F.H.S., M.A.C.D., J.d.M., J.A., H.D., M.M., M.J.K., P.J.v.S., M.N.A.B.K., G.H.M.v.P., B.S., A.C.F., I.B., J.K.)., van Dam AD; Division of Endocrinology, Department of Medicine, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, the Netherlands (A.D.D., P.C.N.R.)., de Bruin G; Department of Chemical Biology, Leiden Institute of Chemistry, the Netherlands (G.d.B., B.I.F.)., Depuydt MAC; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, the Netherlands (F.H.S., M.A.C.D., J.d.M., J.A., H.D., M.M., M.J.K., P.J.v.S., M.N.A.B.K., G.H.M.v.P., B.S., A.C.F., I.B., J.K.)., de Mol J; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, the Netherlands (F.H.S., M.A.C.D., J.d.M., J.A., H.D., M.M., M.J.K., P.J.v.S., M.N.A.B.K., G.H.M.v.P., B.S., A.C.F., I.B., J.K.)., Amersfoort J; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, the Netherlands (F.H.S., M.A.C.D., J.d.M., J.A., H.D., M.M., M.J.K., P.J.v.S., M.N.A.B.K., G.H.M.v.P., B.S., A.C.F., I.B., J.K.)., Douna H; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, the Netherlands (F.H.S., M.A.C.D., J.d.M., J.A., H.D., M.M., M.J.K., P.J.v.S., M.N.A.B.K., G.H.M.v.P., B.S., A.C.F., I.B., J.K.)., Meijer M; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, the Netherlands (F.H.S., M.A.C.D., J.d.M., J.A., H.D., M.M., M.J.K., P.J.v.S., M.N.A.B.K., G.H.M.v.P., B.S., A.C.F., I.B., J.K.)., Kröner MJ; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, the Netherlands (F.H.S., M.A.C.D., J.d.M., J.A., H.D., M.M., M.J.K., P.J.v.S., M.N.A.B.K., G.H.M.v.P., B.S., A.C.F., I.B., J.K.)., van Santbrink PJ; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, the Netherlands (F.H.S., M.A.C.D., J.d.M., J.A., H.D., M.M., M.J.K., P.J.v.S., M.N.A.B.K., G.H.M.v.P., B.S., A.C.F., I.B., J.K.)., Bernabé Kleijn MNA; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, the Netherlands (F.H.S., M.A.C.D., J.d.M., J.A., H.D., M.M., M.J.K., P.J.v.S., M.N.A.B.K., G.H.M.v.P., B.S., A.C.F., I.B., J.K.)., van Puijvelde GHM; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, the Netherlands (F.H.S., M.A.C.D., J.d.M., J.A., H.D., M.M., M.J.K., P.J.v.S., M.N.A.B.K., G.H.M.v.P., B.S., A.C.F., I.B., J.K.)., Florea BI; Department of Chemical Biology, Leiden Institute of Chemistry, the Netherlands (G.d.B., B.I.F.)., Slütter B; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, the Netherlands (F.H.S., M.A.C.D., J.d.M., J.A., H.D., M.M., M.J.K., P.J.v.S., M.N.A.B.K., G.H.M.v.P., B.S., A.C.F., I.B., J.K.)., Foks AC; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, the Netherlands (F.H.S., M.A.C.D., J.d.M., J.A., H.D., M.M., M.J.K., P.J.v.S., M.N.A.B.K., G.H.M.v.P., B.S., A.C.F., I.B., J.K.)., Bot I; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, the Netherlands (F.H.S., M.A.C.D., J.d.M., J.A., H.D., M.M., M.J.K., P.J.v.S., M.N.A.B.K., G.H.M.v.P., B.S., A.C.F., I.B., J.K.)., Rensen PCN; Division of Endocrinology, Department of Medicine, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, the Netherlands (A.D.D., P.C.N.R.)., Kuiper J; Division of BioTherapeutics, Leiden Academic Centre for Drug Research, the Netherlands (F.H.S., M.A.C.D., J.d.M., J.A., H.D., M.M., M.J.K., P.J.v.S., M.N.A.B.K., G.H.M.v.P., B.S., A.C.F., I.B., J.K.).
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2024 Jun; Vol. 44 (6), pp. 1346-1364. Date of Electronic Publication: 2024 Apr 25.
DOI:	10.1161/ATVBAHA.123.319701
Abstrakt:	Background: 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. Methods: 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. Results: 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. Conclusions: 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. Competing Interests: Disclosures None.
Databáze:	MEDLINE
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