ADP-ribosylation in experimental atherosclerosis: a potential link between dyslipidemia and inflammation in cardiovascular disease

ABSTRACT: Multimodal inflammation and lipid accumulation are major features of atherosclerosis, a leading cause of death and morbidity worldwide. Our previous study recognized ADP-ribosylation, a post-translational modification, as a novel regulator of macrophage-induced inflammation and atherogenesis.2 Our recent ADP-ribosylome study using an acute inflammation mouse model demonstrated that systemic IFN-gamma administration induced changes to the ADP-ribosylation of lipid-binding and macrophage-associated proteins in the liver and spleen of wild-type mice, respectively. We also identified ADP-ribosylated apolipoproteins A-I and A-II (APOA1, APOA2) in the liver of wild-type mice. In this current study, we investigated the ADP-ribosylome of the atherosclerotic aorta derived from low-density lipoprotein receptor-deficient (Ldlr-/-) mice. Mice were fed a regular chow diet or a high-fat diet (HFD) for 3 or 6 months before harvesting the aorta, liver, and plasma. ADP-ribosylome enrichment from mouse aorta presented several challenges that were overcome by pooling 10 aortae per diet/month group, and applying our unique and recently optimized ion mobility mass spectrometry strategy to increase ADP-ribosyl peptide signals. The increased prevalence of ADP-ribosylated apolipoproteins in both liver and aorta of HFD-fed mice suggests that the liver secreted them as lipoproteins which eventually accumulated in the aorta. In particular, ADP-ribosylation sites predominated the C-terminus of APOA1. As C-terminal helices of APOA1 are important for lipid binding, engagement of ABCA1 in smaller HDL particles, and the interaction of lipid-free APOA1 with macrophages and specific lipid efflux, disturbance in the ADP-ribosylation of this region could impair the protein’s functions.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver, Aorta

DISEASE(S): Atherosclerosis

SUBMITTER: Sasha Singh  

LAB HEAD: Masanori Aikawa

PROVIDER: PXD051108 | Pride | 2025-09-19

REPOSITORIES: Pride