Mechanism Of Iron Metabolism Abnormality Affecting Aortic Dissection

BackgroundThe pathogenesis of aortic dissection remains unclear.The aim of the present study was to establish whether iron deficiency(ID)regulates the function of vascular smooth muscle cells(VSMCs)during the development of aortic dissection(AD).In addition,the contribution of mitochondrial towards this process was ascertained.Through Serological analysis of clinical patients,we found that serum iron levels in patients with aortic dissection were significantly lower than those in the control group.However,how serum iron deficiency affects the occurrence of aortic dissection is still unclear.Studies have shown that iron can affect mitochondrial function,so we speculate that iron can cause medial aortic degeneration by affecting mitochondrial function.MethodsAscending aorta tissue was obtained from AD patients and organ donors.We use Elastic van Gieson staining and Masson staining to observe aorta form and structure,prussian blue staining method to detect human aortic iron levels,immunohistochemical(IHC)to detect transferrin(TF),transferrin receptor(TFRC)expression,immunofluorescence staining(IF)for alpha-smooth muscle actin(alpha SMA),myosin light chain(MLC),cytochrome c(cyt c),Caspase 9 and 8-hydroxy-2-deoxyguanine nucleoside(8-OHd G)detection and the proteins were observed by western blotting(WB).The morphological changes of human aortic mitochondria were observed by transmission electron microscopy(TEM).Next,the model mice were fed a special diet containing different combinations of either iron deficiency or alpha-amino-propionitrile(BAPN)and the mouse aorta was obtained under different pathological conditions.The staining was used to verify the level of modeling,followed by ATP level testing to assess mitochondrial function.Then,we using ferrous sulfate and deferoxamine(DFO)intervention in vascular smooth muscle cells(VSMCs),and detect the absorption of iron and iron levels by WB test cells,test ATP level and mitochondrial function by ATP test and JC-1,through the ROS flow detection,H2O2 detection and LDH levels to verify after the intervention levels of oxidative stress in cells,streaming through the apoptosis of intervention to detect cell apoptosis,and through the WB and IF method to detect the protein and hypoxia inducing factor alpha 1 alpha(HIF-1α)the expression of quantity.Finally,as in previous cell experiments,we added the HIF-1α inhibitor LW6 to interfere with cells to verify the effect of iron on mitochondria and VSMCs.ResultsIron levels in patients with aortic dissection were significantly lower than those in the control group,and the corresponding TF and TFRC levels were increased.The expression of VSMC contractility α-SMA and MLC decreased and mitochondrial morphology changed.Animal experiments show that compared with the control group,although the EVG staining and Masson staining results,there is no obvious change in aortic structure after the ID intervention,but further tests revealed that TF and TFRC increased,alpha SMA and MLC decreases after ID treatment,this is similar to a single BAPN intervention,but the degree of change is lower than the single BAPN intervention,and the ID + BAPN tissue morphology and protein expression changes are more obvious after intervention.The results of ATP detection showed that the content of ATP in the aorta of each group was control group > BAPN group and ID group > BAPN+ID group.In addition,mitochondrial damage and oxidative stress level of mice in the ID group and the BAPN group were increased,and mice in the ID+BAPN group were increased the most.Cell experiments showed that cell expression of α-SMA and MLC in the DFO group significantly decreased,oxidative stress level significantly increased,expression of mitochondrial damage-related proteins increased,ATP activity and mitochondrial membrane potential significantly decreased,and cell apoptosis rate increased.At the same time,HIF-1α increased in this group.After the addition of LW6,the related cell changes caused by ID were inhibited,the oxidative stress level of cells was reduced,and the expression of mitochondrial damage-related proteins was decreased compared with that of the DFO group.Reviewing the associated changes in model mice and humans,we found that iron deficiency caused elevated HIF-1α,while aortic tissue samples from mice and humans confirmed cellular damage caused by mitochondrial damage in the ruptured aorta.ConclusionsIron deficiency can inhibit the degradation of hif-1 in the body,cause intracellular mitochondrial damage and release of cyt c,activate caspase-9 and trigger subsequent online reaction,and induce the accumulation of 8-OHd G in the nucleus,thus leading to cell apoptosis and necrosis.However,the injury and apoptosis of VSMCs in the aortic wall leads to the destruction of the aortic structure and weakened contractility, making aortic dissection more prone to occur.