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. 2021 Dec 23:8:743519.
doi: 10.3389/fcvm.2021.743519. eCollection 2021.

Angiopoietin 2 as a Novel Potential Biomarker for Acute Aortic Dissection

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Angiopoietin 2 as a Novel Potential Biomarker for Acute Aortic Dissection

Bi Huang et al. Front Cardiovasc Med. .

Abstract

Biomarker-assisted diagnosis of acute aortic dissection (AAD) is important for initiation of treatment and improved survival. However, identification of biomarkers for AAD in blood is a challenging task. The present study aims to find the potential AAD biomarkers using a transcriptomic strategy. Arrays based genome-wide gene expression profiling were performed using ascending aortic tissues which were collected from AAD patients and healthy donors. The differentially expressed genes were validated using quantitative reverse transcriptase PCR (qRT-PCR) and western blot. The plasma levels of a potential biomarker, angiopoietin 2 (ANGPT2) were determined in case-control cohort (77 AAD patients and 82 healthy controls) by enzyme linked immunosorbent assay. Receiver operating characteristic curve (ROC) was used to evaluate the diagnostic power of ANGPT2 for AAD. Transcriptome data demonstrated that a total of 18 genes were significantly up-regulated and 28 genes were significantly down-regulated among AAD tissues (foldchange>3.0, p < 0.01). By bioinformatic analysis, we identified ANGPT2 as a candidate biomarker for blood-based detection of AAD. The qRT-PCR and protein expression demonstrated that ANGPT2 increased 2.4- and 4.2 folds, respectively in aortic tissue of AAD patients. Immunohistochemical staining demonstrated that ANGPT2 was markedly increased in intima of the aortic wall in AAD. Furthermore, ANGPT2 was significantly elevated in AAD patients as compared with controls (median 1625 vs. 383 pg/ml, p < 1E-6). ROC curve analysis showed that ANGPT2 was highly predictive of a diagnosis of type A AAD (area under curve 0.93, p < 1E-6). Sensitivity and specificity were 81 and 90%, respectively at the cutoff value of 833 pg/ml. In conclusion, ANGPT2 could be a promising biomarker for diagnosis of AAD; however, more studies are still needed to verify its specificity in diagnosing of AAD.

Keywords: acute aortic dissection; angiopoietin 2; biomarker; diagnosis; transcriptome.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
A heatmap was generated by clustering based on probes differentially expressed in dissected aortas as compared with normal aortas. The gene associated with each probe is indicated to the right of the heatmap.
Figure 2
Figure 2
Validation of expression changes of ANGPT2 and CCL3 in transcription and protein level. (A): Validation of microarray data by quantitative Real-Time PCR (qRT-PCR). The expression patterns of ANGPT2 and CCL3 increased 2.4-fold (P < 0.01) and 3.6-fold (P = 0.02) in aortic tissues of AAD compared with healthy control. GAPDH was used as housekeeping gene. **: P < 0.01, *: P < 0.05. (B,C): Western blot for ANGPT2 and CCL3 protein from aortic tissues of healthy control and AAD patients. β-actin serves as an internal control. ANGPT2 increased up to 4.2 folds in AAD patients, whereas CCL3 did not change.
Figure 3
Figure 3
Aortic pathology of AAD patients and healthy controls. The elastic fibers were properly oriented in control aortas and laminar medial necrosis, inflammation, and giant cells were not present in healthy controls (A–C). In contrast, the aorta wall tissues were loosely structured and disordered in AAD patients. The dissected aortas were found medial degeneration, as shown by loss of smooth muscle cells and elastic fibers, and proteoglycan accumulation in the medial layer of the aorta (D–F). Arrows indicated the lumen side. HE, hematoxylin-eosin; EVG, elastica van Gieson's; Masson, Masson's trichrome. Magnification: ×100. AAD, acute aortic dissection.
Figure 4
Figure 4
Immunohistochemical staining. Ascending aorta specimen in the entry site of the dissection from AAD patients were sectioned and labeled with ANGPT2. (A–C), control aortas exhibited a weaker signal of ANGPT2. (D–F), Intense ANGPT2 signals were presented in the thoracic aortic dissection patient. Arrows indicate examples of ANGPT2 positive cells. HC, healthy control; AAD, acute aortic dissection; magnification: × 200.
Figure 5
Figure 5
Plasma levels of ANGPT2 in healthy control (n = 82), Type A Dissection (n = 77). Data are expressed as scatter plots respresenting the median, 25 and 75 percentiles. Statistical analysis: Mann-Whitney non-parametric test.
Figure 6
Figure 6
ROC analysis of ANGPT2.

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