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Urine proteome analysis reflects atherosclerotic disease in an ApoE-/- mouse model and allows the discovery of new candidate biomarkers in mouse and human atherosclerosis.
- Source :
-
Molecular & cellular proteomics : MCP [Mol Cell Proteomics] 2012 Jul; Vol. 11 (7), pp. M111.013847. Date of Electronic Publication: 2012 Feb 27. - Publication Year :
- 2012
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Abstract
- 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.
- Subjects :
- Animals
Apolipoproteins E genetics
Atherosclerosis diagnosis
Atherosclerosis etiology
Atherosclerosis genetics
Biomarkers urine
Diet, High-Fat adverse effects
Disease Progression
Electrophoresis, Capillary
Humans
Mass Spectrometry
Mice
Mice, Knockout
Peptides urine
Plaque, Atherosclerotic diagnosis
Plaque, Atherosclerotic etiology
Plaque, Atherosclerotic genetics
Proteome metabolism
Sensitivity and Specificity
Sequence Analysis, Protein
Apolipoproteins E deficiency
Atherosclerosis urine
Collagen Type I urine
Epidermal Growth Factor urine
Plaque, Atherosclerotic urine
alpha 1-Antitrypsin urine
Subjects
Details
- Language :
- English
- ISSN :
- 1535-9484
- Volume :
- 11
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Molecular & cellular proteomics : MCP
- Publication Type :
- Academic Journal
- Accession number :
- 22371488
- Full Text :
- https://doi.org/10.1074/mcp.M111.013847