Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China; Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
J Proteomics. 2023 May 30;280:104889. doi: 10.1016/j.jprot.2023.104889. Epub 2023 Mar 24.
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.
蛋白质赖氨酸琥珀酰化是一种新发现的翻译后修饰。本研究探讨了蛋白质赖氨酸琥珀酰化在主动脉瘤和夹层（AAD）发病机制中的作用。使用 4D 无标记 LC-MS/MS 分析对从 5 名心脏移植供体、5 名胸主动脉瘤（TAA）患者和 5 名胸主动脉夹层（TAD）患者获得的主动脉进行了全局琥珀酰化谱分析。与正常对照组相比，我们在 TAA 中检测到 314 种蛋白质中的 1138 个琥珀酰化位点，在 TAD 中检测到 381 种蛋白质中的 1499 个琥珀酰化位点。其中，TAA 和 TAD 之间有 76 个蛋白质的 120 个差异琥珀酰化位点重叠（|log2FC| > 0.585，p < 0.05）。这些差异修饰的蛋白质主要定位于线粒体和细胞质中，主要参与多种能量代谢过程，包括碳代谢、氨基酸分解代谢和脂肪酸的β氧化。通过建立血管平滑肌细胞中赖氨酸琥珀酰化的体外模型，我们观察到三种关键代谢酶（PKM、LDHA 和 SDHA）活性的变化。这些发现表明，琥珀酰化可能有助于主动脉疾病的发病机制，并为研究琥珀酰化在 AAD 中的功能作用和调节机制提供了有价值的资源。意义：AAD 是相互关联的危及生命的疾病，发病率和死亡率都很高。尽管我们发现 AAD 患者的主动脉组织中赖氨酸琥珀酰化显著上调，但它在主动脉疾病进展中的作用在很大程度上尚不清楚。我们进行了 4D 无标记 LC-MS/MS 分析，与正常对照组相比，在 TAA 和 TAD 之间，有 76 个蛋白质的 120 个差异琥珀酰化位点重叠。赖氨酸琥珀酰化可能通过调节能量代谢途径有助于 AAD 的发病机制。含有琥珀酰化位点的蛋白质可以作为主动脉疾病的潜在诊断标志物和治疗靶点。
