The Researches Of Aortic Dissection With Metabolomics And The Effects Of L-Cysteine In The Occurrence Of Aortic Dissection

Objectives Aortic dissection is one of the most life-threatening and devastating cardiovascular diseases,while the pathogenesis is still poorly understood,and more researches are still in need for better prevention and therapy of the disease.Metabolomics,the comprehensive quantitative analysis of all the metabolites of an organism or specified biological sample,can provide metabolic profiles which contain the information of genetic and environmental effects such as diets,life style,gut flora metabolism and so on,which cannot be obtained directly from the genome,the transcriptome,or the proteome.Those metabolites have also been found that might act as risk indicators,biomarkers,therapeutic effects,or even crucial roles in the mechanisms of the diseases.Metabolomics has already been widely used in the research of cardiovascular diseases.In our research,we firstly explored the metabolome of aortic dissection by metabolomics,then selected the most promising metabolites for further research,in order to get a better understanding in the prevention,diagnosis and therapy of aortic dissection.Methods Serum samples from patients of aortic dissection,aortic aneurysm and volunteers were newly collected,and tested by Gas chromatography-time of flight-mass spectrometer(GC/TOF-MS).After data analysis the metabolic profiles of changed metabolites between groups were obtained,and we chose L-cysteine(Cys)as the most promising metabolite in aortic dissection.First,we quantified the metabolic enzyme of Cys,cystathionine-γ-lyase(CSE),in the aorta of aortic dissection patients and normal donors.Then,we applied the mice model of aortic dissection by subcutaneous implantation of micropumps which contained angiotensin II(Ang II).With the interventions of different reagents in micropumps and diets,we set negative control group,normal model group and high Cys group in order to assess the incidence of aortic dissection and extent of vascular remodeling.Finally,we carried the cell experiment with human aortic smooth muscle cell(HASMC)in order to illustrate the molecule mechanism of the effects of Cys in aortic dissection.We up-regulated and down-regulated Cys by addition of exogenous Cys and DL-propargylglycine(PAG)respectively,and examined the proliferation,apoptosis and reactive oxygen species(ROS)of HASMC,so as to explore the molecular mechanism that Cys affected the occurance of aortic dissection.Results The metabolomics of serum samples showed a difference of 7 main metabolites between aortic dissection and nomal control.Among them,threonine,methionine and Cys were found different in aortic dissection group between both aortic aneurysm and normal group.Besides,glutamine,citrulline and lactic acid were also found different expressed.Those metabolites involved in the metabolism of homocysteine,oxidative stress injury,urea cycle and energy metabolism.In the further verification of Cys,we found a decline of CSE in the aorta of aortic dissection,it may also indicate the decrease of Cys in tissue.The animal experiment showed a significant reduce of the incidence of aortic dissection in high Cys group than normal model group(1/19 vs 7/19,P=0.042).Besides,Cys can also alleviate the vascular remodeling.In the cell experiment,up-regulation of Cys can reduce the proliferation of HASMC,and opposite tendency could be seen when down-regulated Cys with PAG.Under the condition of oxidative stress,Cys can decrease the production of ROS and reduce the rate of apoptosis,which can also be reversed by PAG.Conclusions We applied the metabolomics in the research of aortic dissection for the first time,and successfully obtained the metabolites profiles and metabolic character.Those differences of metabolites represented the metabolic disturbance of homocysteine,resistance to oxidative stress damage,urea cycle and abnormal of energy metabolism in aortic dissection.Some of them could be new targets in the research of the disease.In the verification of target metabolite Cys,we proved the abnormal metabolism of Cys in the aorta of aortic dissection patients.The animal and cell experiments revealed that the metabolism of Cys could be intervened and Cys might be protective factor for aortic dissection,by inhibiting the proliferation of HASMC,decreasing the production of ROS and reducing the apoptosis of cells under oxidative stress condition.Cys can alleviate the vascular remodeling of aorta,maintain the stabilization and integrity of structure,so as to reduce the incidence of aortic dissection in mice model.The metabolic disorder of Cys might be risk factor and biomarker of aortic dissection,and its potential protective effect presented a new way in the prevention and therapy of the disease by intervention of Cys metabolism.