Yang Hang, Yang Fangfang, Luo Mingyao, Chen Qianlong, Liu Xuanyu, Zhang Yinhui, Zhu Guoyan, Chen Wen, Li Tianjiao, Shu Chang, Zhou Zhou
State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
State Key Laboratory of Cardiovascular Disease, Center of Vascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Front Cardiovasc Med. 2022 Feb 8;9:826861. doi: 10.3389/fcvm.2022.826861. eCollection 2022.
Thoracic aortic dissection (TAD) is a life-threatening disease with no effective drug therapy thus far. New therapeutic targets and indications for timely surgical intervention are urgently needed. Our aim is to investigate new pathological mechanisms and potential biomarkers of TAD through global metabolomic profiling of aortic aneurysm and dissection patients.
We performed untargeted metabolomics to determine plasma metabolite concentrations in an aortic disease cohort, including 70 thoracic aortic aneurysm (TAA) and 70 TAD patients, as well as 70 healthy controls. Comparative analysis revealed that sphingolipid, especially its core metabolite C18-ceramide, was significantly distinguished in TAD patients but not in TAA patients, which was confirmed by subsequent quantitative analysis of C18-ceramide in a validation cohort. By analyzing our existing multiomics data in aortic tissue in a murine TAD model and TAD patients, we found that an enhanced ceramide synthesis pathway in macrophages might contribute to the elevated ceramide. Inhibition of the ceramide synthesis pathway by myriocin markedly alleviated BAPN-induced aortic inflammation and dissection in mice. studies demonstrated that exogenous C18-ceramide promoted macrophage inflammation and matrix metalloprotein (MMP) expression through the NLRP3-caspase 1 pathway. In contrast, inhibition of endogenous ceramide synthesis by myriocin attenuated lipopolysaccharide (LPS)-induced macrophage inflammation.
Our findings demonstrated that ceramide metabolism disturbance might play a vital role in TAD development by aggravating aortic inflammation through the NLRP3 pathway, possibly providing a new target for pharmacological therapy and a potential biomarker of TAD.
胸主动脉夹层（TAD）是一种危及生命的疾病，目前尚无有效的药物治疗方法。迫切需要新的治疗靶点和及时进行手术干预的指征。我们的目的是通过对主动脉瘤和夹层患者进行全面的代谢组学分析，研究TAD新的病理机制和潜在生物标志物。
我们对一个主动脉疾病队列进行了非靶向代谢组学研究，以确定血浆代谢物浓度，该队列包括70例胸主动脉瘤（TAA）患者、70例TAD患者以及70名健康对照者。比较分析显示，鞘脂尤其是其核心代谢物C18-神经酰胺在TAD患者中显著不同，但在TAA患者中并非如此，随后在验证队列中对C18-神经酰胺进行定量分析证实了这一点。通过分析我们在小鼠TAD模型和TAD患者的主动脉组织中现有的多组学数据，我们发现巨噬细胞中增强的神经酰胺合成途径可能导致神经酰胺升高。用myriocin抑制神经酰胺合成途径可显著减轻小鼠中BAPN诱导的主动脉炎症和夹层。研究表明，外源性C18-神经酰胺通过NLRP3-半胱天冬酶1途径促进巨噬细胞炎症和基质金属蛋白酶（MMP）表达。相反，myriocin抑制内源性神经酰胺合成可减轻脂多糖（LPS）诱导的巨噬细胞炎症。
我们的研究结果表明，神经酰胺代谢紊乱可能通过NLRP3途径加重主动脉炎症，在TAD发展中起关键作用，可能为药物治疗提供新靶点和TAD的潜在生物标志物。
