Tandem mass tag-based quantitative proteomic analysis identification of succinylation related proteins in pathogenesis of thoracic aortic aneurysm and aortic dissection

doi:10.7717/peerj.15258

. 2023 May 11:11:e15258.

doi: 10.7717/peerj.15258. eCollection 2023.

Tandem mass tag-based quantitative proteomic analysis identification of succinylation related proteins in pathogenesis of thoracic aortic aneurysm and aortic dissection

Yu Zhang^#¹, Hongwei Zhang^#^{1

2}, Haiyue Wang¹, Chenhao Wang¹, Peng Yang¹, Chen Lu¹, Yu Liu¹, Zhenyuan Xu¹, Yi Xie¹, Jia Hu^{1

2

3}

Affiliations

¹ Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China.
² Department of Cardiovascular Surgery, Guang'an Hospital of West China Hospital of Sichuan University, Guang'an, China.
³ Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, China.

^# Contributed equally.

PMID: 37193023
PMCID: PMC10183161
DOI: 10.7717/peerj.15258

Tandem mass tag-based quantitative proteomic analysis identification of succinylation related proteins in pathogenesis of thoracic aortic aneurysm and aortic dissection

Yu Zhang et al. PeerJ. 2023.

. 2023 May 11:11:e15258.

doi: 10.7717/peerj.15258. eCollection 2023.

Authors

Yu Zhang^#¹, Hongwei Zhang^#^{1

2}, Haiyue Wang¹, Chenhao Wang¹, Peng Yang¹, Chen Lu¹, Yu Liu¹, Zhenyuan Xu¹, Yi Xie¹, Jia Hu^{1

2

3}

Affiliations

¹ Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China.
² Department of Cardiovascular Surgery, Guang'an Hospital of West China Hospital of Sichuan University, Guang'an, China.
³ Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, China.

^# Contributed equally.

PMID: 37193023
PMCID: PMC10183161
DOI: 10.7717/peerj.15258

Abstract

Background: Thoracic aortic aneurysm and dissection (TAAD) are devastating cardiovascular diseases with a high rate of disability and mortality. Lysine succinylation, a newly found post-translational modification, has been reported to play an important role in cardiovascular diseases. However, how succinylation modification influences TAAD remains obscure.

Methods: Ascending aortic tissues were obtained from patients with thoracic aortic aneurysm (TAA, n = 6), thoracic aortic dissection (TAD) with pre-existing aortic aneurysm (n = 6), and healthy subjects (n = 6). Global lysine succinylation level was analyzed by Western blotting. The differentially expressed proteins (DEPs) were analyzed by tandem mass tag (TMT) labeling and mass spectrometry. Succinylation-related proteins selected from the literature review and AmiGO database were set as a reference inventory for further analysis. Then, the pathological aortic sections were chosen to verify the proteomic results by Western blotting and qRT-PCR.

Results: The level of global lysine succinylation significantly increased in TAA and TAD patients compared with healthy subjects. Of all proteins identified by proteomic analysis, 197 common DEPs were screened both in TAA and TAD group compared with the control group, of which 93 proteins were significantly upregulated while 104 were downregulated. Among these 197 DEPs, OXCT1 overlapped with the succinylation-related proteins and was selected as the target protein involved in thoracic aortic pathogenesis. OXCT1 was further verified by Western blotting and qRT-PCR, and the results showed that OXCT1 in TAA and TAD patients was significantly lower than that in healthy donors (p < 0.001), which was consistent with the proteomic results.

Conclusions: OXCT1 represents novel biomarkers for lysine succinylation of TAAD and might be a therapeutic target in the future.

Keywords: OXCT1; Proteomics; Succinylation; Tandem mass tag labelling; Thoracic aortic aneurysm; Thoracic aortic dissection.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**Figure 1. Protein lysine succinylation significantly increased in TAA and TAD tissues.**
Western blotting results of lysine succinylation (A), ubiquitination (B), malonylation (C), acetylation (D), and lactylation (E). (F) Coomassie brilliant blue staining. TAA, thoracic aortic aneurysm. TAD, thoracic aortic dissection.

**Figure 2. Proteomic analysis of the aortic samples.**
(A) Principal component analysis (PCA) of proteome data. (B) Expression heat map of all the proteins from TAA patients, TAD patients and healthy subjects. (C) Volcano plots of proteins in ascending aortic tissues from TAA patients and healthy subjects. (D) Volcano plots of proteins in ascending aortic tissues from TAD patients and healthy subjects. (E and F) Overlap evaluation of DEPs in three groups. TAA, thoracic aortic aneurysm. TAD, thoracic aortic dissection. DEPs, differentially expressed proteins.

**Figure 3. The Gene Ontology (GO) enrichment of differentially expressed proteins (DEPs).**
(A) Pie chart of the GO enrichment analysis results sorted by protein counts (top 10). (B) Columnar section of the GO enrichment analysis results sorted by −log P-value (top 15).

**Figure 4. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for differentially expressed proteins (DEPs).**
(A) The bubble chart of the KEGG pathway enrichment analysis results. (B) The cnetplot of the KEGG pathway enrichment analysis results.

**Figure 5. Identification and verification of OXCT1.**
(A) Venn diagram of succinylation-related DEPs. (B and C) OXCT1 expression in pathological sections of TAA patients, TAD patients and healthy controls by Western blotting and qRT-PCR. (*P < 0.001 vs healthy control group) TAA, thoracic aortic aneurysm. TAD, thoracic aortic dissection. DEPs, differentially expressed proteins.

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1. Clément M, Chappell J, Raffort J, Lareyre F, Vandestienne M, Taylor AL, Finigan A, Harrison J, Bennett MR, Bruneval P, Taleb S, Jørgensen HF, Mallat Z. Vascular smooth muscle cell plasticity and autophagy in dissecting aortic aneurysms. Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;39(6):1149–1159. doi: 10.1161/ATVBAHA.118.311727. - DOI - PMC - PubMed

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[1] Andreata F, Syvannarath V, Clement M, Delbosc S, Guedj K, Fornasa G, Khallou-Laschet J, Morvan M, Even G, Procopio E, Gaston AT, Le Borgne M, Deschamps L, Nicoletti A, Caligiuri G. Macrophage CD31 signaling in dissecting aortic aneurysm. Journal of the American College of Cardiology. 2018;72(1):45–57. doi: 10.1016/j.jacc.2018.04.047. - DOI - PubMed

[2] Andreata F, Syvannarath V, Clement M, Delbosc S, Guedj K, Fornasa G, Khallou-Laschet J, Morvan M, Even G, Procopio E, Gaston AT, Le Borgne M, Deschamps L, Nicoletti A, Caligiuri G. Macrophage CD31 signaling in dissecting aortic aneurysm. Journal of the American College of Cardiology. 2018;72(1):45–57. doi: 10.1016/j.jacc.2018.04.047. - DOI - PubMed

[3] Bai W, Cheng L, Xiong L, Wang M, Liu H, Yu K, Wang W. Protein succinylation associated with the progress of hepatocellular carcinoma. Journal of Cellular and Molecular Medicine. 2022;26(22):5702–5712. doi: 10.1111/jcmm.17507. - DOI - PMC - PubMed

[4] Bai W, Cheng L, Xiong L, Wang M, Liu H, Yu K, Wang W. Protein succinylation associated with the progress of hepatocellular carcinoma. Journal of Cellular and Molecular Medicine. 2022;26(22):5702–5712. doi: 10.1111/jcmm.17507. - DOI - PMC - PubMed

[5] Carbon S, Ireland A, Mungall CJ, Shu SQ, Marshall B, Lewis S. AmiGO: online access to ontology and annotation data. Bioinformatics. 2009;25(2):288–289. doi: 10.1093/bioinformatics/btn615. - DOI - PMC - PubMed

[6] Carbon S, Ireland A, Mungall CJ, Shu SQ, Marshall B, Lewis S. AmiGO: online access to ontology and annotation data. Bioinformatics. 2009;25(2):288–289. doi: 10.1093/bioinformatics/btn615. - DOI - PMC - PubMed

[7] Chung J, Lachapelle K, Wener E, Cartier R, De Varennes B, Fraser R, Leask RL. Energy loss, a novel biomechanical parameter, correlates with aortic aneurysm size and histopathologic findings. The Journal of Thoracic and Cardiovascular Surgery. 2014;148(3):1082–1088. doi: 10.1016/j.jtcvs.2014.06.021. - DOI - PubMed

[8] Chung J, Lachapelle K, Wener E, Cartier R, De Varennes B, Fraser R, Leask RL. Energy loss, a novel biomechanical parameter, correlates with aortic aneurysm size and histopathologic findings. The Journal of Thoracic and Cardiovascular Surgery. 2014;148(3):1082–1088. doi: 10.1016/j.jtcvs.2014.06.021. - DOI - PubMed

[9] Clément M, Chappell J, Raffort J, Lareyre F, Vandestienne M, Taylor AL, Finigan A, Harrison J, Bennett MR, Bruneval P, Taleb S, Jørgensen HF, Mallat Z. Vascular smooth muscle cell plasticity and autophagy in dissecting aortic aneurysms. Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;39(6):1149–1159. doi: 10.1161/ATVBAHA.118.311727. - DOI - PMC - PubMed

[10] Clément M, Chappell J, Raffort J, Lareyre F, Vandestienne M, Taylor AL, Finigan A, Harrison J, Bennett MR, Bruneval P, Taleb S, Jørgensen HF, Mallat Z. Vascular smooth muscle cell plasticity and autophagy in dissecting aortic aneurysms. Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;39(6):1149–1159. doi: 10.1161/ATVBAHA.118.311727. - DOI - PMC - PubMed

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Tandem mass tag-based quantitative proteomic analysis identification of succinylation related proteins in pathogenesis of thoracic aortic aneurysm and aortic dissection

Affiliations

Tandem mass tag-based quantitative proteomic analysis identification of succinylation related proteins in pathogenesis of thoracic aortic aneurysm and aortic dissection

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