Biology subjects

von Scheidt, M.

Publications and source records attributed to von Scheidt, M..

6 recordsLinked to original sources

bioRxiv2026

Intraindividual longitudinal changes of the proteome reveal dynamic markers of biological aging

Proteomic aging clocks have emerged as biomarkers of aging, but most rely on cross-sectional data. Here, we present a proteomic aging clock based on longitudinal measurements of liquid chromatography-mass spectrometry plasma proteomics at up to three time points in the population-based KORA cohort, comprising 9,105 samples from 4,100 individuals in the final dataset aged 25-88 years. The model predicts chronological age and yields a measure of proteomic age acceleration associated with lifestyle and clinical risk factors. Risk factor-stratified analyses reveal shared proteomic signatures among cardiometabolic exposures and distinct signatures for smoking and physical activity. Within individuals, dyslipidemia and impaired kidney function track transitions to increases in age acceleration, while higher age acceleration is associated with increased all-cause mortality. Mediation analysis suggests that risk factors are linked to mortality indirectly through age acceleration. Affected proteins and pathways highlight extracellular matrix remodeling, complement and coagulation pathways, and liver-derived plasma proteins as key contributors to aging. Mendelian randomization identifies proteins with evidence consistent with a causal role in aging-related traits. Together, these findings are consistent with biological aging being dynamically responsive to changes in modifiable risk factors.

bioinformatics↗

bioRxiv2026

A cell type-resolved proteomic atlas of the human body

Proteins define what cells do, yet their systematic quantification across human cell types has remained out of reach. Using Deep Visual Proteomics on tissue from a healthy female donor, we built an atlas of 27 cell types across 14 tissues, quantifying two-thirds of all human protein-coding genes, with up to 8,500 per population. The proteome partitions bimodally into a universal core and highly specialized programs. Integration into the Human Protein Atlas Single Cell Resource enabled comparison of RNA and protein abundance at cell type resolution, revealing that concordance depends on pathway rather than cellular identity. This resolution uncovered cancer-testis antigens in oocytes invisible to bulk profiling. Our openly accessible resource provides a foundation for cell type-resolved proteomics in health and disease.

biochemistry↗

bioRxiv2026

Polyploid cardiomyocytes define disease-specific transcriptional states in the mammalian heart

The adult mammalian heart has a limited regenerative capacity. Following injury, cardiomyocytes undergo a hypertrophic response accompanied by polyploidization, which has been described as a barrier to proliferation and regeneration of the heart1,2. However, the unique molecular programs of polyploidy, or genome multiplied cardiomyocytes, and their influence on the disease-related myocardial remodelling process remains unclear. Here, we integrate single-nuclei and high-resolution spatial multi-omics across human, rat, and mouse hearts to define novel cardiac cell states and their tissue niches in ischemic and non-ischemic heart disease. Computational analysis across scales allowed us to generate detailed networks of the cardiac tissue remodelling process as well as tissue and sub-cellular environments uniquely enriched in polyploid cardiomyocytes or their diploid origins. We identify a conserved, dichotomous transcriptional program distinguishing diploid from polyploid cardiomyocytes. Polyploid cardiomyocytes demonstrated rewired metabolic and chromatin-remodeling transcriptional programs and recapitulate the gene signature of immature human fetal cardiomyocytes. Notably, we observe that polyploid cardiomyocytes--rather than the general myocyte population--are the primary sites of enrichment for major heart-failure drug targets, including the mineralocorticoid, {beta}1-adrenergic, and glucagon-like peptide-1 receptors. Based on our cross-species dataset we further identified TNIK, a Wnt-pathway regulator expressed in polyploid cardiomyocytes across species, as a potential therapeutic target and demonstrate that pharmacological TNIK inhibition improves cardiac function after myocardial infarction in rats. Together, this species-spanning, disease-resolved study redefines cardiomyocyte heterogeneity in heart disease and suggests a therapeutic path to heart failure treatment by targeting polyploid cardiomyocytes.

genomics↗

bioRxiv2026

Cancer drives atherosclerotic plaque vulnerability by inducing pathological angiogenesis

Cardiovascular disease (CVD) is the leading cause of death for many cancer survivors, a phenomenon traditionally attributed to shared risk factors and cardiotoxic chemotherapies. Here, we hypothesized that cancer may also directly promote atherosclerosis. Propensity-matched analyses confirmed significantly elevated cardiovascular event rates amongst cancer patients, independent of comorbidities such as smoking. Atheroprone mice implanted with colorectal tumors demonstrated accelerated features of plaque vulnerability, driven by pathological angiogenesis and intraplaque hemorrhage. Mechanistically, tumor-secreted TNF- induced the pro-angiogenic factor LRG1 across multiple murine models and human plaques. Therapeutic interventions targeting these pathways, including with FDA-approved cytokine inhibitors or tumor resection, prevented plaque destabilization in mice and reduced coronary revascularization rates in patients. Together, these findings suggest that cancer may causally promote CVD and unveil novel translational strategies for cancer survivors.

pathology↗

bioRxiv2025

Cigarette smoking upregulates vascular expression of the novel atherosclerosis risk factor ADAMTS-7

BackgroundCigarette smoking is an established risk factor for coronary artery disease (CAD) and myocardial infarction. Genetic variants in the extracellular matrix protease ADAMTS-7 were also identified to increase CAD risk. Notably, ADAMTS7 represents the only genomic locus that revealed a gene-environment interaction with smoking. The underlying mechanisms of this interaction remain unclear. Methods and ResultsIn a murine model, cigarette smoke exposure (CSE) led to an upregulation of vascular ADAMTS7 expression in wild type (WT) C57BL/6J mice. ADAMTS7 upregulation was also found in carotid plaques from ever-smokers undergoing carotid endarterectomy in humans. Bulk RNA sequencing of lung tissues from WT mice exposed to CS revealed a downregulation of 20 and an upregulation of 173 transcripts. Among upregulated transcripts in smoking-exposed lungs, we found C-C motif chemokine ligand 17 (CCL17), which was likewise upregulated in plasma from smoking mice and humans. In vitro, recombinant CCL17 upregulated ADAMTS7 expression in primary vascular smooth muscle cells (VSMC), which was inhibited secondary to silencing of CCL17s bona fide receptor C-C Motif Chemokine Receptor 4 (CCR4). Conditioned media from CCL17-stimulated VSMC lacking ADAMTS-7 showed reduced release of inflammatory cytokines by endothelial cells (EC), reduced EC activation, and monocyte-to-EC adhesion. In proatherogenic Apoe-/- mice exposed to CS, more numerous neutrophils, inflammatory monocytes, and macrophages were found in atherosclerotic plaques as compared to room air exposition. This effect was blunted in Apoe-/-Adamts7-/- mice. ConclusionsFor the first time, our findings link CSE to vascular inflammation via CCL17-mediated upregulation of the CAD risk factor ADAMTS7 and provide a mechanistic explanation for the gene-environment interaction between CS and ADAMTS7 in CAD. Targeting ADAMTS-7 might be a promising therapeutic strategy irrespective of smoking status. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/685237v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1d8366eorg.highwire.dtl.DTLVardef@1dda3feorg.highwire.dtl.DTLVardef@39a4bcorg.highwire.dtl.DTLVardef@6e58b6_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2023

The novel coronary artery disease risk factor ADAMTS-7 modulates atherosclerotic plaque formation by degradation of TIMP-1

BackgroundThe ADAMTS7 locus was genome-wide significantly associated with coronary artery disease (CAD). Lack of the extracellular matrix (ECM) protease ADAMTS-7 was shown to reduce atherosclerotic plaque formation. ObjectiveTo identify molecular mechanisms and downstream targets of ADAMTS-7 mediating risk of atherosclerosis. MethodsTargets of ADAMTS-7 were identified by high-resolution mass spectrometry of atherosclerotic plaques from Apoe-/- and Apoe-/-Adamts7-/- mice. ECM proteins were identified using solubility profiling. Putative targets were validated using immunofluorescence, in vitro degradation assays, co-immunoprecipitation, and Forster resonance energy transfer (FRET)-based protein-protein interaction assays. ADAMTS7 expression was measured in fibrous caps of human carotid artery plaques. ResultsIn humans, ADAMTS7 expression was higher in caps of unstable as compared to stable carotid plaques. Compared to Apoe-/- mice, atherosclerotic aortas of Apoe-/- mice lacking Adamts-7 (Apoe-/-Adamts7-/-) contained higher protein levels of tissue inhibitor of metalloproteases 1 (Timp-1). In co-immunoprecipitation experiments, the catalytic domain of ADAMTS-7 bound to TIMP-1, which was degraded in the presence of ADAMTS-7 in vitro. ADAMTS-7 reduced the inhibitory capacity of TIMP-1 at its canonical target matrix metalloprotease 9 (MMP-9) As a downstream mechanism, we investigated collagen content in plaques of Apoe-/- and Apoe-/-Adamts7-/- mice after Western diet. Picrosirius red staining of the aortic root revealed less collagen as a readout of higher MMP-9 activity in Apoe-/- as compared to Apoe-/- Adamts7-/- mice. In order to facilitate high-throughput screening for ADAMTS-7 inhibitors with the aim to decrease TIMP-1 degradation, we designed a FRET-based assay targeting the ADAMTS-7 catalytic site. ConclusionADAMTS-7, which is induced in unstable atherosclerotic plaques, decreases TIMP-1 stability reducing its inhibitory effect on MMP-9, which is known to promote collagen degradation and is likewise genome-wide significantly associated with CAD. Disrupting the interaction of ADAMTS-7 and TIMP-1 might be a strategy to increase collagen content and plaque stability for reduction of atherosclerosis-related events.

molecular biology↗