Activated Protein C Regulates The Formation And Progression Of Aortic Dissection Via The Adaptor Protein P66Shc

Background and Objective:Activated protein C has a role to protect cells in various disease models.The cytoprotection of a PC is related with antioxygenation.P66 Shc is an important redox state preceptor protein,the transposition from cytoplasm to mitochondria of which can improve ROS production in mitochondria.Current studies show that endotheliocyte damage induced by oxidative stress and tunica media of artery lesion induced by inflammatory cell infiltration are important factors in AD formation and development.Therefore,to investigate the regulation and mechanism of activated protein C in the AD formation and progression via the adaptor protein p66 Shc will contribute to a more knowledge of pathogenesis of AD.Methods:Plasma and Aorta tissue samples in AD patients and in healthy persons were collected,and every medical records including gender,age,body weight,BP were collected,too.ELISA was performed to detect the a PC activity in each group.The tissue was sectioned and then HE staining,ROS staining was performed.The total protein and RNA was extracted,and the expression of p66 Shc,and PCNA in human aorta tissue was analyzed by Western blot and Real-time PCR.Ang II-induced Aortic dissection model in Apo E mice were successfully established and dectected contents of the a PC.The BP and aortic echocardiography graph were recorded.The aorta tissue were collected for HE staining.The total RNA was extracted,and the expression of p66 Shc in Apo E mice was analyzed by Real-time PCR。HUVEC was treated by Ang II to generate in vitro model of AD.Western blot and Real-time PCR was performed to detect the expression of p66Shc、PCNA to analyze the expression profile by Ang II concentration and time.The a PC pre-incubated cells were then treated by Ang II,to analyzed the regulation mechanism of Ang II-induced p66 Shc and PCNA,ROS expression.Results:Aortic injuries(true or false lumen)were found in AD patients.The a PC activity was reduced in AD patients while p66 Shc,PCNA and ROS expression were increased.Ang II-induced Aortic dissection model in Apo E-/-mice was successfully established.The significant rising in blood pressure,broadening in aortic diameters,false lumen of aorta and thrombosis were observed.P66 Shc gene expression was increased in aortic tissue.Ang II(10-7mol/L)significantly up-regulated the expression of p66 Shc,PCNA in HUVEC,and this regulation is time-dependent.The Ang II-induced p66 Shc,PCNA,ROS expression was suppressed by a PC or PC pre-incubation.Conclusion:The content of a PC in AD patient plasma is significantly decreased compared to the control group.While the production of adaptor protein p66 Shc in artery tissue sections of AD patients is significantly increased.And we got the similar result in the analysis of mouse samples in mouse AD models.Ang II can upregulate the p66 Shc expression in HUVECs in in-vitro,a PC inhibit the up-regulation induced by Ang II in HUVECs.From this we can assume that the decline of the content of endogenous a PC and the over expression of adaptor protein p66 Shc in artery tissue are important mechanism of AD formation and development.The results of the current study suggests that a novel diagnostic and therapeutic role for a PC against aortic dissection.