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Proteomic signatures of serum albumin-bound proteins from stroke patients with and without endovascular closure of PFO are significantly different and suggest a novel mechanism for cholesterol efflux.

Lopez MF, Krastins B, Sarracino DA, Byram G, Vogelsang MS, Prakash A, Peterman S, Ahmad S, Vadali G, Deng W, Inglessis I, Wickham T, Feeney K, Dec GW, Palacios I, Buonanno FS, Lo EH, Ning M - Clin Proteomics (2015)

Bottom Line: The method used in this study combined albumin immuno-enrichment with high resolution LC-MS in order to specifically capture and quantify the albumin-bound proteins.Eight proteins, typically associated with HDL were common to both sample sets and quantitatively differently abundant.In addition, the results suggest that PFO endovascular closure can potentially have effects on HDL, cholesterol and albumin-bound ApoA-I abundance, therefore possibly providing benefits in cardioprotective functions.

View Article: PubMed Central - PubMed

Affiliation: Thermo Scientific BRIMS, 790 Memorial Dr, Cambridge, MA 02139 UK.

ABSTRACT

Background: The anatomy of PFO suggests that it can allow thrombi and potentially harmful circulatory factors to travel directly from the venous to the arterial circulation - altering circulatory phenotype. Our previous publication using high-resolution LC-MS/MS to profile protein and peptide expression patterns in plasma showed that albumin was relatively increased in donor samples from PFO-related than other types of ischemic strokes. Since albumin binds a host of molecules and acts as a carrier for lipoproteins, small molecules and drugs, we decided to investigate the albumin-bound proteins (in a similar sample cohort) in an effort to unravel biological changes and potentially discover biomarkers related to PFO-related stroke and PFO endovascular closure.

Methods: The method used in this study combined albumin immuno-enrichment with high resolution LC-MS in order to specifically capture and quantify the albumin-bound proteins. Subsequently, we measured cholesterol and HDL in a larger, separate cohort of PFO stroke patients, pre and post closure.

Results: The results demonstrated that a number of proteins were specifically associated with albumin in samples with and without endovascular closure of the PFO, and that the protein profiles were very different. Eight proteins, typically associated with HDL were common to both sample sets and quantitatively differently abundant. Pathway analysis of the MS results suggested that enhanced cholesterol efflux and reduced lipid oxidation were associated with PFO closure. Measurement of total cholesterol and HDL in a larger cohort of PFO closure samples using a colorimetric assay was consistent with the proteomic predictions.

Conclusions: The collective data presented in this study demonstrate that analysis of albumin-bound proteins could provide a valuable tool for biomarker discovery on the effects of PFO endovascular closure. In addition, the results suggest that PFO endovascular closure can potentially have effects on HDL, cholesterol and albumin-bound ApoA-I abundance, therefore possibly providing benefits in cardioprotective functions.

No MeSH data available.


Related in: MedlinePlus

IPA downstream analysis of differently abundant albumin-bound proteins in PFO closurevsno-closure sample sets. The IPA biological function downstream analysis is based on z-score and p-value. In our analyses, the z-score values indicated that a function was expected to be increased (positive z-score) or decreased (negative z-score) in PFO closure relative to no-closure samples.
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Fig3: IPA downstream analysis of differently abundant albumin-bound proteins in PFO closurevsno-closure sample sets. The IPA biological function downstream analysis is based on z-score and p-value. In our analyses, the z-score values indicated that a function was expected to be increased (positive z-score) or decreased (negative z-score) in PFO closure relative to no-closure samples.

Mentions: The protein datasets were analyzed by IPA Downstream Analysis. The IPA biological downstream analysis is based on z-score and p-value (see Methods). Biological functions defined in the IPA knowledge database that are expected to be increased or decreased according to the protein abundance in the dataset are identified by the z-score algorithm and the score reflects the significance of the prediction (the Z-scores do not measure the amount of increase or decrease of a function). In our analyses, the z-score values indicated that a function was expected to be increased (positive z-score) or decreased (negative z-score) in PFO closure relative to no-closure samples. The probability that the association between the proteins in our datasets and a related biological function defined in the IPA knowledge database was considered significant if the p-value was ≤0.01 as determined by using Fisher’s exact T test. The results from the IPA downstream analysis predicted an increase (z-score >2.0) in PFO closure vs no-closure in several functional categories. The most significant function was cholesterol efflux, with p-values of 2.33E-09, 2.41E-11 in the PFO closure and no-closure data sets, respectively and z-scores of 2.73 and 2.37 in the PFO closure and no-closure data sets, respectively (Figure 3). Conversely, the analysis predicted a decrease in lipid oxidation with a z-score of −2.06 and a p-value 1.65E-04 in PFO closure samples. There was no significant value for decreased lipid oxidation in the no-closure samples (Figure 3). This analysis suggests increased cholesterol and phospholipid efflux and decreased lipid oxidation in the PFO closure sample group as compared to the no closure sample group.Figure 3


Proteomic signatures of serum albumin-bound proteins from stroke patients with and without endovascular closure of PFO are significantly different and suggest a novel mechanism for cholesterol efflux.

Lopez MF, Krastins B, Sarracino DA, Byram G, Vogelsang MS, Prakash A, Peterman S, Ahmad S, Vadali G, Deng W, Inglessis I, Wickham T, Feeney K, Dec GW, Palacios I, Buonanno FS, Lo EH, Ning M - Clin Proteomics (2015)

IPA downstream analysis of differently abundant albumin-bound proteins in PFO closurevsno-closure sample sets. The IPA biological function downstream analysis is based on z-score and p-value. In our analyses, the z-score values indicated that a function was expected to be increased (positive z-score) or decreased (negative z-score) in PFO closure relative to no-closure samples.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4305391&req=5

Fig3: IPA downstream analysis of differently abundant albumin-bound proteins in PFO closurevsno-closure sample sets. The IPA biological function downstream analysis is based on z-score and p-value. In our analyses, the z-score values indicated that a function was expected to be increased (positive z-score) or decreased (negative z-score) in PFO closure relative to no-closure samples.
Mentions: The protein datasets were analyzed by IPA Downstream Analysis. The IPA biological downstream analysis is based on z-score and p-value (see Methods). Biological functions defined in the IPA knowledge database that are expected to be increased or decreased according to the protein abundance in the dataset are identified by the z-score algorithm and the score reflects the significance of the prediction (the Z-scores do not measure the amount of increase or decrease of a function). In our analyses, the z-score values indicated that a function was expected to be increased (positive z-score) or decreased (negative z-score) in PFO closure relative to no-closure samples. The probability that the association between the proteins in our datasets and a related biological function defined in the IPA knowledge database was considered significant if the p-value was ≤0.01 as determined by using Fisher’s exact T test. The results from the IPA downstream analysis predicted an increase (z-score >2.0) in PFO closure vs no-closure in several functional categories. The most significant function was cholesterol efflux, with p-values of 2.33E-09, 2.41E-11 in the PFO closure and no-closure data sets, respectively and z-scores of 2.73 and 2.37 in the PFO closure and no-closure data sets, respectively (Figure 3). Conversely, the analysis predicted a decrease in lipid oxidation with a z-score of −2.06 and a p-value 1.65E-04 in PFO closure samples. There was no significant value for decreased lipid oxidation in the no-closure samples (Figure 3). This analysis suggests increased cholesterol and phospholipid efflux and decreased lipid oxidation in the PFO closure sample group as compared to the no closure sample group.Figure 3

Bottom Line: The method used in this study combined albumin immuno-enrichment with high resolution LC-MS in order to specifically capture and quantify the albumin-bound proteins.Eight proteins, typically associated with HDL were common to both sample sets and quantitatively differently abundant.In addition, the results suggest that PFO endovascular closure can potentially have effects on HDL, cholesterol and albumin-bound ApoA-I abundance, therefore possibly providing benefits in cardioprotective functions.

View Article: PubMed Central - PubMed

Affiliation: Thermo Scientific BRIMS, 790 Memorial Dr, Cambridge, MA 02139 UK.

ABSTRACT

Background: The anatomy of PFO suggests that it can allow thrombi and potentially harmful circulatory factors to travel directly from the venous to the arterial circulation - altering circulatory phenotype. Our previous publication using high-resolution LC-MS/MS to profile protein and peptide expression patterns in plasma showed that albumin was relatively increased in donor samples from PFO-related than other types of ischemic strokes. Since albumin binds a host of molecules and acts as a carrier for lipoproteins, small molecules and drugs, we decided to investigate the albumin-bound proteins (in a similar sample cohort) in an effort to unravel biological changes and potentially discover biomarkers related to PFO-related stroke and PFO endovascular closure.

Methods: The method used in this study combined albumin immuno-enrichment with high resolution LC-MS in order to specifically capture and quantify the albumin-bound proteins. Subsequently, we measured cholesterol and HDL in a larger, separate cohort of PFO stroke patients, pre and post closure.

Results: The results demonstrated that a number of proteins were specifically associated with albumin in samples with and without endovascular closure of the PFO, and that the protein profiles were very different. Eight proteins, typically associated with HDL were common to both sample sets and quantitatively differently abundant. Pathway analysis of the MS results suggested that enhanced cholesterol efflux and reduced lipid oxidation were associated with PFO closure. Measurement of total cholesterol and HDL in a larger cohort of PFO closure samples using a colorimetric assay was consistent with the proteomic predictions.

Conclusions: The collective data presented in this study demonstrate that analysis of albumin-bound proteins could provide a valuable tool for biomarker discovery on the effects of PFO endovascular closure. In addition, the results suggest that PFO endovascular closure can potentially have effects on HDL, cholesterol and albumin-bound ApoA-I abundance, therefore possibly providing benefits in cardioprotective functions.

No MeSH data available.


Related in: MedlinePlus