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. 2020 Jul 2:2020:1068402.
doi: 10.1155/2020/1068402. eCollection 2020.

TMT-Based Quantitative Proteomic Analysis Identification of Integrin Alpha 3 and Integrin Alpha 5 as Novel Biomarkers in Pathogenesis of Acute Aortic Dissection

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TMT-Based Quantitative Proteomic Analysis Identification of Integrin Alpha 3 and Integrin Alpha 5 as Novel Biomarkers in Pathogenesis of Acute Aortic Dissection

Lingyu Xing et al. Biomed Res Int. .

Abstract

Background: Acute aortic dissection (AAD) is a devastating cardiovascular disease with a high rate of disability and mortality. This disease often rapidly progresses to fatal multiple organ hypoperfusion, and the incidence has been increasing in recent years. However, the molecular mechanisms have yet to be clarified. This study is aimed at identifying the differential abundance proteins (DAPs) of aortic arch tissues in patients with AAD by proteomics and select possible proteins involved in AAD pathogenesis.

Methods: The fresh aortic arch tissues obtained from 5 AAD patients and 1 healthy donor were analyzed by amine-reactive tandem mass tag (TMT) labelling and mass spectrometry; then, the pathological sections of another 10 healthy donors and 20 AAD patients were chosen to verify the proteomic results by immunohistochemistry.

Results: Of 809 proteins identified by proteomic analysis, 132 differential abundance proteins (DAPs) were screened, of which 100 proteins were significantly downregulated while 32 upregulated. Among 100 downregulated proteins, two proteins with known function, integrin alpha 3 (ITGA-3) and ITGA-5, were selected as target proteins involved in AAD pathogenesis. Two target DAPs were verified by immunohistochemisty, and the results showed that the integrated option density (IOD) of ITGA-3 and ITGA-5 in AAD patients was significantly lower than that in healthy donors, which were consistent with the proteomic results (P < 0.001).

Conclusion: ITGA-3 and ITGA-5 represent novel biomarkers for the pathogenesis of AAD and might be a therapeutic target in the future.

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Conflict of interest statement

The authors declare that there is no conflict of interest regarding the publication of this article.

Figures

Figure 1
Figure 1
Experimental flowchart. The aortic arch tissues of 5 patients with AAD were extracted during surgery. The peptides labelled with TMT were prepared, and a MS/MS analysis was performed. The proteomic data were analyzed, and the DAPs were selected and verified by immunohistochemistry.
Figure 2
Figure 2
Principal component analysis (PCA) and heat map of proteome data. (a) Principal component analysis of the proteome data in a 2D graph of PC1 and PC2. (b) Expression heat map of the proteome data in the samples.
Figure 3
Figure 3
The Gene Ontology (GO) enrichment of 132 differential abundance proteins (DAPs). (a) Sorted by descending order of the number of protein associated with the listed GO ID. (b) Sorted by descending order of P value for the GO enrichment terms. Because of the limited number of patients, we considered DAPs as meaningful only as strong differently expressed (∣log2FC | >2).
Figure 4
Figure 4
Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for 132 DAPs between health donor vs. patients. (a) Top 30 significantly enriched pathways were shown in the senior bubble chart. The rich factor is the ratio of DAP numbers annotated in this pathway term to all gene numbers annotated in this pathway term (P < 0.01). (b) Most of downregulated DAPs (n = 16/51) were found in the PI3K-AKT signaling pathway.
Figure 5
Figure 5
The protein-protein interaction networks is analyzed by string software. Different line colours represent the types of evidence used in predicting the associations: gene fusion (red), neighborhood (green), cooccurrence across genomes (blue), coexpression (black), experimental (purple), association in curated databases (light blue), or comentioned in PubMed abstracts (yellow).
Figure 6
Figure 6
The biomarkers (ITGA-3, ITGA-5) verified by immunohistochemistry (IHC). (a) The black arrows present positive signals of ITGA-3 and ITGA-5 staining by DAB in healthy donors. Negative control: the section was stained with secondary antibodies only. Scale bars = 200 μm. (b) The IODs of ITGA-3 and ITGA-5 in AAD patients were significantly lower compared with healthy donors (∗∗∗P < 0.001).

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