Urine Proteome Analysis Reflects Atherosclerotic Disease in an ApoE−/− Mouse Model and Allows the Discovery of New Candidate Biomarkers in Mouse and Human Atherosclerosis
| Autor: | Eric Schiffer, Alexander Iphöfer, Yung C. Chen, Constantin von zur Mühlen, Karlheinz Peter, Andreas Zirlik, Christoph Bode, Nay M. Htun, Lothar Jänsch, Petra Zürbig, Irene Neudorfer, Christine Sackmann, Harald Mischak |
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| Rok vydání: | 2012 |
| Předmět: |
Apolipoprotein E
Proteome Urinary system Urine 030204 cardiovascular system & hematology Biology Diet High-Fat Bioinformatics Proteomics Sensitivity and Specificity Biochemistry Collagen Type I Mass Spectrometry Analytical Chemistry Mice 03 medical and health sciences Apolipoproteins E 0302 clinical medicine Sequence Analysis Protein Epidermal growth factor medicine Animals Humans Molecular Biology 030304 developmental biology Mice Knockout 0303 health sciences Kidney Epidermal Growth Factor Research Electrophoresis Capillary Atherosclerosis Molecular biology Plaque Atherosclerotic 3. Good health medicine.anatomical_structure alpha 1-Antitrypsin Disease Progression Immunohistochemistry Peptides Biomarkers |
| Zdroj: | Scopus-Elsevier Molecular & Cellular Proteomics; Vol 11 Molecular & Cellular Proteomics |
| ISSN: | 1535-9476 |
| Popis: | Noninvasive diagnosis of atherosclerosis via single biomarkers has been attempted but remains elusive. However, a previous polymarker or pattern approach of urine polypeptides in humans reflected coronary artery disease with high accuracy. The aim of the current study is to use urine proteomics in ApoE(-/-) mice to discover proteins with pathophysiological roles in atherogenesis and to identify urinary polypeptide patterns reflecting early stages of atherosclerosis. Urine of ApoE(-/-) mice either on high fat diet (HFD) or chow diet was collected over 12 weeks; urine of wild type mice on HFD was used to exclude diet-related proteome changes. Capillary electrophoresis coupled to mass spectrometry (CE-MS) of samples identified 16 polypeptides specific for ApoE(-/-) mice on HFD. In a blinded test set, these polypeptides allowed identification of atherosclerosis at a sensitivity of 90% and specificity of 100%, as well as monitoring of disease progression. Sequencing of the discovered polypeptides identified fragments of α(1)-antitrypsin, epidermal growth factor (EGF), kidney androgen-regulated protein, and collagen. Using immunohistochemistry, α(1)-antitrypsin, EGF, and collagen type I were shown to be highly expressed in atherosclerotic plaques of ApoE(-/-) mice on HFD. Urinary excretion levels of collagen and α(1)-antitrypsin fragments also significantly correlated with intraplaque collagen and α(1)-antitrypsin content, mirroring plaque protein expression in the urine proteome. To provide further confirmation that the newly identified proteins are relevant in humans, the presence of collagen type I, α(1)-antitrypsin, and EGF was also confirmed in human atherosclerotic disease. Urine proteome analysis in mice exemplifies the potential of a novel multimarker approach for the noninvasive detection of atherosclerosis and monitoring of disease progression. Furthermore, this approach represents a novel discovery tool for the identification of proteins relevant in murine and human atherosclerosis and thus also defines potential novel therapeutic targets. |
| Databáze: | OpenAIRE |
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