👤 Mary S Rouse

Hypertensive disorders of pregnancy (HDP) are associated with future cardiovascular disease but mechanisms are not well defined. We examined the association between HDP and atherosclerotic cardiovascular disease (ASCVD) biomarkers 5-10 years after childbirth. Secondary analysis of the NICHD MFMU Network Gestational Diabetes (GDM) Trial Follow-Up study. Participants were recruited and biospecimens obtained 5-10 years after the original trial of treatment for mild GDM. Patients were included if a biospecimen was available and their HDP status was known. We compared patients who experienced HDP to normotensive controls. Outcomes included unadjusted medians and mean concentrations of ASCVD serum biomarkers Apolipoprotein B (ApoB), high-sensitivity C-reactive protein (hs-CRP), and creatinine. Generalized linear models were used to compare concentrations between groups. Of 740 participants in this analysis, 78 had been diagnosed with HDP. Mean duration of follow up after delivery was 7.1 ± 1.3 years for both groups. Unadjusted means of each biomarker were not different between groups. After adjusting for obesity, mean serum creatinine was elevated in women who had been diagnosed with HDP (0.77 mg/dL 95%CI (0.72, 0.82)) compared to controls (0.71 mg/dL 95%CI (0.69, 0.72)), p = 0.02. Adjusted means for ApoB between women with HDP and controls were 64.2 mg/dL (95%CI (59.3, 69.5)) and 60.6 mg/dL (95%CI (58.9, 62.3)), (p = 0.18), and for hs-CRP mg/L were 14.6 (95%CI (11.4, 19.1)) and 14.5 mg/L (95%CI (13.3, 15.9)), (p = 0.91). In patients with HDP compared to normotensive controls, serum creatinine, but not ApoB or hs-CRP, was modestly elevated within 10 years of childbirth. Show less

Lipoprotein lipase (LPL) is the rate-limiting enzyme responsible for hydrolyzing triglycerides in circulating lipoproteins. Reduced LPL activity contributes to hypertriglyceridemia, a major cardiovascular risk factor. LPL activity is thought to depend on the conformation of the lid domain, the lipid pore, N- and C-terminal domains (NTD, CTD), and stabilization of these domains by endogenous activators such as apolipoprotein C-II (ApoC-II). Despite major clinical significance, the structure-function relationship of LPL's functional domains and cofactors remain incompletely understood. To address this, we performed the longest known (1-μs) molecular dynamics simulations of LPL independently and in complex with an ApoC-II mimetic peptide (ApoC-II-P). For the first time, we show that LPL's flexible lid can adopt multiple orientations, transitioning between open and closed states that regulate lipid pore access and catalytic activity. We also observed 'flipping' of ~180° by the CTD, a unique characteristic that dictates LPL activity when not in a closed lid state. Furthermore, ApoC-II-P stabilizes LPL by bridging its NTD and CTD, while maintaining an optimal lid orientation. Biochemical and cellular assays corroborate these findings, demonstrating that ApoC-II-P enhances LPL hydrolysis and supports noncanonical LPL functions. Together, these insights reveal previously unrecognized mechanisms governing LPL regulation and activity dynamics. Show less

During infection with the Lyme arthritis (LA) pathogen Borrelia burgdorferi, T-cell responses to both host and pathogen are dysregulated, resulting in chronic infection and frequent development of autoimmunity. To assess CD4+ T-cell epitopes presented during development of LA, we used an unbiased, immunopeptidomics approach to characterize the major histocompatibility complex (MHC) class II immunopeptidome in B burgdorferi-infected C57BL/6 (B6) mice, which develop mild, self-limiting LA, and infected B6 Il10-/- mice, which develop severe, persistent LA at 0, 4, and 16 weeks postinfection (22-23 mice per group). Peptides derived from proteins involved in adaptive T- and B-cell responses and cholesterol metabolism, including human Lyme autoantigen apolipoprotein B-100 (apoB-100), were enriched in infected Il10-/- mice; whereas peptides derived from proteins involved in neutrophil extracellular net formation were enriched in infected B6 mice. Presentation of apoB-100 peptides showed evidence of epitope expansion during infection. Of several identified B burgdorferi peptides, only 1, a methyl-accepting chemotaxis protein peptide Mcp4442-462, was immunogenic. ApoB-100, a human Lyme autoantigen, undergoes marked epitope expansion during LA development. The paucity of immunogenic B burgdorferi epitopes supports previous findings suggesting CD4+ T-cell responses are suppressed in murine LA. Show less