Pyruvate Kinase M2 Activator TEPP-46 Suppresses The Formation Of Thoracic Aortic Aneurysm And Dissection

Background and Objective:Thoracic aortic aneurysm and dissection(TAAD)is a kind of lethal cardiovascular diseases.Owing to the infiltration of inflammatory cells such as monocytes/macrophages and the activation of inflammasome,a large number of cytokines,chemical factors and matrix metalloproteinases are released,which aggravates the occurrence and development of TAAD.Activation of the glycolysis rate-limiting enzyme-related gene PKM2 exacerbates sepsis by increasing the secretion of the inflammatory factor IL-1β.Therefore,we explored whether TEPP-46,a PKM2 agonist,could reduce the activation of inflammasome and the secretion of IL-1β by influencing the activation of PKM2,delaying the occurrence and development of TAAD.Methods and Results:We induced wild-type C57/B6 mice by BAPN(β-aminopropionitrile fumaric acid)(1g/kg/day)to establish a TAAD model.The expression of PKM2 gene was detected by collecting tissue samples from TAAD patients,normal patients,TAAD mice and normal mice.Survival rate,mortality rate and morbidity of mice in blank control group,BAPN model group and TEPP-46(5 mg/kg/2 day)treatment group were counted.The diameter of thoracic aorta was examined by ultrasonography on 21 and 28 days after model establishment.Statistical results showed that compared with BAPN model group,the survival rate of mice in TEPP-46 treatment group was improved,mortality and morbidity were significantly reduced,and the degree of thoracic aorta dilatation was significantly decreased.Histological staining results showed that the structure of thoracic aorta in TEPP-46 treated mice was obviously protected,the structure of aorta was normal,the defect of vascular smooth muscle was alleviated,the structure of elastic fibrin was intact,and the deposition of collagen was weakened.ROS activation,MMPs,IL-1β andinflammatory cell infiltration were reduced,especially in monocytes and macrophages,and the activation of NLRP3 inflammasome-related pathways were significantly suppressed.The supernatants of thoracic aorta and peripheral blood of mice were detected by RT-qPCR,WB and Elisa.The results showed that the activation of NLRP3 inflammatory bodies and the secretion of IL-1β were decreased in TEPP-46 treatment group compared with BAPN model group.Conclusion:Inflammasome mediated by glycolytic rate-limiting enzymes-related genes PKM2 and NLRP3 play an important role in the occurrence and development of TAAD.PKM2 agonist TEPP-46 can alleviate the occurrence and development of TAAD by inhibiting the activation of PKM2 and reducing the secretion of IL-1β mediated by NLRP3 Inflammasome.This discovery can provide new ideas for the treatment and prevention of thoracic aortic aneurysm and dissection.