Abstract
High-density lipoproteins (HDLs) are complex protein and lipid assemblies whose composition is known to change in diverse pathological situations. Analysis of the HDL proteome can thus provide insight into the main mechanisms underlying abdominal aortic aneurysm (AAA) and potentially detect novel systemic biomarkers. We performed a multiplexed quantitative proteomics analysis of HDLs isolated from plasma of AAA patients (N = 14) and control study participants (N = 7). Validation was performed by western-blot (HDL), immunohistochemistry (tissue), and ELISA (plasma). HDL from AAA patients showed elevated expression of peroxiredoxin-6 (PRDX6), HLA class I histocompatibility antigen (HLA-I), retinol-binding protein 4, and paraoxonase/arylesterase 1 (PON1), whereas α-2 macroglobulin and C4b-binding protein were decreased. The main pathways associated with HDL alterations in AAA were oxidative stress and immune-inflammatory responses. In AAA tissue, PRDX6 colocalized with neutrophils, vascular smooth muscle cells, and lipid oxidation. Moreover, plasma PRDX6 was higher in AAA (N = 47) than in controls (N = 27), reflecting increased systemic oxidative stress. Finally, a positive correlation was recorded between PRDX6 and AAA diameter. The analysis of the HDL proteome demonstrates that redox imbalance is a major mechanism in AAA, identifying the antioxidant PRDX6 as a novel systemic biomarker of AAA.
Highlights
The most convenient source of a systemic abdominal aortic aneurysm (AAA) biomarker is blood plasma
We focused on PRDX6 because it reflects the generalized alteration in proteins implicated in redox homeostasis, the functional category most clearly changed in the high-density lipoproteins (HDLs) proteome of AAA patients
It is important to note that the small size of HDLs means that all the proteins detected and quantified by mass spectrometry are unlikely to reside in the same particle simultaneously
Summary
The most convenient source of a systemic AAA biomarker is blood plasma. Our group and others have previously analyzed AAA patient plasma using a variety of proteomics approaches[5,6,7,8,9]. The high dynamic range of protein concentrations in plasma makes it difficult to quantify proteins present in low amounts, even after depletion of the most abundant proteins To circumvent this problem, some authors have concentrated on the analysis of specific plasma subproteomes, such as high-density lipoproteins (HDLs). Screening of the HDL proteome has identified dramatic protein alterations in a variety of disease contexts, including cardiovascular diseases[11,12,13,14,15]. HDLs have several important cardiovascular protective properties, including anti-oxidant, anti-inflammatory, and antithrombotic effects[16,17]. We previously demonstrated impaired anti-proteolytic[18] and anti-oxidative functions[19] in HDLs from human AAA This effect has been linked to altered HDL protein composition or to impaired function of individual components. Circulating levels of PRDX6 are increased in AAA-patient plasma, and PRDX6 levels correlate positively with AAA size, identifying PRDX6 as a promising biomarker of AAA
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