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Background ApoAI (apolipoproteins AI) and apoAII (apolipoprotein AII) are structural and functional proteins of high‐density lipoproteins (HDL) which undergo post‐translational modifications at specific residues, creating distinct proteoforms. While specific post‐translational modifications have been reported to alter apolipoprotein function, the full spectrum of apoAI and apoAII proteoforms and their associations with cardiometabolic phenotype remains unknown. Herein, we comprehensively characterize apoAI and apoAII proteoforms detectable in serum and their post‐translational modifications and quantify their associations with cardiometabolic health indices. Methods and Results Using top‐down proteomics (mass‐spectrometric analysis of intact proteins), we analyzed paired serum samples from 150 CARDIA (Coronary Artery Risk Development in Young Adults) study participants from year 20 and 25 exams. Measuring 15 apoAI and 9 apoAII proteoforms, 6 of which carried novel post‐translational modifications, we quantified associations between percent proteoform abundance and key cardiometabolic indices. Canonical (unmodified) apoAI had inverse associations with HDL cholesterol and HDL‐cholesterol efflux, and positive associations with obesity indices (body mass index, waist circumference), and triglycerides, whereas glycated apoAI showed positive associations with serum glucose and diabetes mellitus. Fatty‐acid‒modified ApoAI proteoforms had positive associations with HDL cholesterol and efflux, and inverse associations with obesity indices and triglycerides. Truncated and dimerized proteoforms of apoAII were associated with HDL cholesterol (positively) and obesity indices (inversely). Several proteoforms had no significant associations with phenotype. Conclusions Associations between apoAI and AII and cardiometabolic indices are proteoform‐specific. These results provide “proof‐of‐concept” that precise chemical characterization of human apolipoproteins will yield improved insights into the complex pathways through which proteins signify and mediate health and disease.

The enzyme, 2′-3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) has been known for over fifty years. Nevertheless, the roles this membrane-bound enzyme play have yet to be described completely. Recently, there has been renewed interest in the study of this enzyme due to studies that suggest that CNPase plays a role in the mediation of cellular inflammatory responses in renal and nervous system tissues. Also, this enzyme, found in oligodendrocytes of the nervous system, has been reported to participate in significant regulatory changes associated with age which may be involved in age-related CNS degeneration. Consequently, development of CNPase inhibitors is of interest and should aid in the study of this, as yet, poorly understood enzyme. In this work we utilized a spectrophotometric enzyme assay to determine the effect a panel of organo-vanadium complexes had on isolated hamster myelin CNPase activity. Our group has now identified several potent in vitro CNPase inhibitors that could prove useful in clarifying the important roles of this enzyme.