Biology subjects

Jokumsen, K. V.

Publications and source records attributed to Jokumsen, K. V..

3 recordsLinked to original sources

bioRxiv2026

Location-dependent proteomics of the aorta reveal an atherosclerotic disease gradient shaped by hemodynamics

Background and aimsAtherosclerotic plaques form preferentially at vascular sites exposed to disturbed blood flow, yet the protein changes underlying this site-specific plaque development remain unclear. Mouse models are widely used to study atherosclerosis but yield only limited amounts of tissue, previously restricting proteomic studies. However, recent advances in mass spectrometry now enable proteomic profiling of very small tissue samples. We aimed to utilise this to uncover site-specific protein changes in aortic regions prone or resistant to plaque formation. MethodsAortic arches from apolipoprotein E-deficient (ApoE-/-) mice fed a Western diet (WD) for 16 weeks were dissected into plaques from the major branches and inner curvature and visibly healthy regions. Proteins were extracted, enzymatically digested, and analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). ResultsMore than 4000 proteins were identified per sample despite their small size (< 1 mg tissue). Principal component analysis showed clustering by both disease status and anatomical location within the aortic arch, indicating distinct proteomes. Proteins known to drive atherosclerosis - including vascular cell adhesion molecule 1 (Vcam1), apolipoprotein B (Apob), lipoprotein lipase (Lpl), and galectin 3 (Lgals3) - were most abundant in advanced plaques and decreased progressively across anatomical regions, reaching their lowest levels in healthy regions furthest from the plaques. Enrichment analysis highlighted pathways related to the extracellular matrix, immune system, hemostasis, and lipoprotein transport as central to disease progression. ConclusionsThis study demonstrates the feasibility of region-resolved proteomics in individual murine aortas and provide new molecular insights into the site-specific nature of atherosclerotic plaque development.

biochemistry↗

bioRxiv2025

Spatial proteomics of the human atherosclerotic microenvironment reveals heterogeneity in intra-plaque proteomes and extracellular matrix remodeling

The heterogeneity of atherosclerotic plaques is critical for their vulnerability to rupture and the associate risk of cardiovascular events. Most proteomic studies have only examined bulk changes, potentially obscuring key spatial differences in protein content and abundance. Here we report a high-resolution spatial proteomics workflow that allows exploration of the molecular landscape of human plaques and murine myocardial tissue. This combines laser capture microdissection of tissue areas (50,000 {micro}m{superscript 2} from 10 {micro}m-thick sections, corresponding to < 30 cells), with high-sensitivity ion-mobility mass spectrometry, allowing spatial profiling of cellular and extracellular matrix (ECM) proteomes. Over 2700 proteins were detected, revealing substantial intra-plaque proteome heterogeneity across distinct regions (lipid-rich, media layers, shoulder regions, necrotic core, intima) and distance from the lumen into the artery wall. Strong inverse correlations were detected between proteases (e.g. cathepsin-B) and core structural ECM components (e.g. perlecan, HSPG2) consistent with active ECM remodeling. Analysis of media layers indicated distinct protein signatures associated with smooth muscle contraction and cell-cell communication. Blood coagulation signatures, including platelet degranulation and fibrin clot formation were enriched at the intimal surface. Inflammatory markers (clusters of differentiation 4 and 68, CD4/CD68; vascular cell adhesion molecular 1, VCAM1) and vascular damage markers (tenascin-C, TNC) were enriched in shoulder regions. The necrotic core was dominated by blood proteins, consistent with intra-plaque hemorrhage. The capacity of this workflow to resolve changes over modest distances (225 {micro}m) provides unprecedented insights into the spatial organisation of the atherosclerotic microenvironment, offering a powerful tool for elucidating plaque biology and identifying potential therapeutic targets.

biochemistry↗

bioRxiv2024

Elevated levels of iodide promote peroxidase-mediated protein iodination and inhibit protein chlorination

At inflammatory sites, immune cells generate oxidants including H2O2. Myeloperoxidase (MPO), released by activated leukocytes employs H2O2 and halide/pseudohalides to form hypohalous acids that mediate pathogen killing. Hypochlorous acid (HOCl) is a major species formed. Excessive or misplaced HOCl formation damages host tissues with this linked to multiple inflammatory diseases. Previously (Redox Biology, 2020, 28, 101331) we reported that iodide (I-) modulates MPO-mediated protein damage by decreasing HOCl generation with concomitant hypoiodous acid (HOI) formation. HOI may however impact on protein structure, so in this study we examined whether and how HOI, from peroxidase/H2O2/I- systems + Cl-, modifies proteins. Experiments employed MPO and lactoperoxidase (LPO) and multiple proteins (serum albumins, anastellin), with both chemical (intact protein and peptide mass mapping, LC-MS) and structural (SDS-PAGE) changes assessed. LC-MS analyses revealed dose-dependent iodination of anastellin and albumins by LPO/H2O2 with increasing I-. Incubation of BSA with MPO/H2O2/Cl- revealed modest chlorination (Tyr286, Tyr475, [~]4%) and Met modification. Lower levels of these species, and extensive iodination at specific Tyr and His residues (>20% modification with >10 {micro}M I-) were detected with increasing I-. Anastellin dimerization was inhibited by increasing I-, but less marked changes were observed with albumins. These data confirm that I- competes with Cl- for MPO and is an efficient HOCl scavenger. These processes decrease protein chlorination and oxidation, but result in extensive iodination. This is consistent with published data on the presence of iodinated Tyr on neutrophil proteins. The biological implications of protein iodination relative to chlorination require further clarification.

biochemistry↗