Global proteomic analysis reveals lysine succinylation contributes to the pathogenesis of aortic aneurysm and dissection

Abstract

Protein lysine succinylation is a recently discovered posttranslational modification. This study examined the role of protein lysine succinylation in the pathogenesis of aortic aneurysm and dissection (AAD). 4D label-free LC-MS/MS analysis was used to perform the global profiles of succinylation in aortas obtained from 5 heart transplant donors, 5 patients with thoracic aortic aneurysm (TAA), and 5 patients with thoracic aortic dissection (TAD). In comparison to normal controls, we detected 1138 succinylated sites from 314 proteins in TAA, and 1499 sites from 381 proteins in TAD. Among these, 120 differentially succinylated sites from 76 proteins overlapped between TAA and TAD (|log2FC| > 0.585, p < 0.05). These differentially modified proteins were mainly localized in the mitochondria and cytoplasm, and were primarily involved in diverse energy metabolic processes, including carbon metabolism, amino acid catabolism, and β-oxidation of fatty acids. By establishing an in vitro model of lysine succinylation in vascular smooth muscle cells, we observed changes in the activities of three key metabolic enzymes (PKM, LDHA, and SDHA). These findings suggest that succinylation potentially contributes to the pathogenesis of aortic diseases, and presents a valuable resource for investigating the functional roles and regulatory mechanisms of succinylation in AAD. SIGNIFICANCE: AAD are interrelated life-threatening diseases associated with high morbidity and mortality. Although we discovered that lysine succinylation was significantly up-regulated in the aorta tissues of patients with AAD, its role in the progression of aortic diseases is largely unknown. We conducted a 4D label-free LC-MS/MS analysis and identified 120 differentially succinylated sites on 76 proteins that overlapped between TAA and TAD as compared to normal controls. Lysine succinylation may contribute to the pathogenesis of AAD by regulating energy metabolism pathways. The proteins containing succinylated sites could be served as potential diagnostic markers and therapeutic targets for aortic diseases.

Keywords: Aortic aneurysm; Aortic dissection; Lysine succinylation; Posttranslational modification; Vascular smooth muscle cells.