Cadmium Exposure Induces Endothelial Dysfunction By Disturbing Lipid Metabolism In Vascular Endothelial Cells

Background: Cadmium is a rare heavy metal that is a major chemical contaminant in the natural and occupational environments of economically developed countries.The biological half-life of cadmium is as long as 10 to 30 years,which causes long-term accumulation in the blood and irreversible damage to the corresponding target organs.The cardiovascular system has been recognized as one of the main target organs for cadmium deposition.A growing body of evidence has been linked to an association between endothelial dysfunction and abnormal lipid metabolism.However,the effects of changes in lipid metabolism on vascular endothelial cells after cadmium exposure are unclear.Objective: This study aimed to investigate whether cadmium can cause endothelial cell dysfunction by interfering with lipid metabolism of vascular endothelial cells,and further study its possible mechanism of action.Methods: Human microvascular endothelial cells(HMEC-1)were exposed to cadmium at different doses and times,resulting in a model of cadmium exposure damage.The cytotoxicity of vascular endothelial cells caused by cadmium was evaluated by changes in CCK-8 and LDH;real-time quantitative PCR of fat metabolism-related genes and detection of changes in triglycerides,total cholesterol and free fatty acids were used to evaluate lipid metabolism caused by cadmium.Changes,while neutral lipid dyes such as Oil Red O and BODIPY were used to observe changes in intracellular lipid droplets;assessment of cadmium-induced endothelial dysfunction by detecting changes in nitric oxide and endothelial nitric oxide synthase levels;Detection of changes in ROS and mitochondrial ROS,mitochondrial membrane potential(MMP)and ATP,and responses to mitochondrial function disorders.Results: Cadmium exposure impeded lipid metabolism in HMEC-1 cells,which was mainly characterized by down-regulation of fat de novo synthesis-related genes(ACACA,FASN,FADS1,PPARG,SREBF1,DGAT1),and up-regulation of fat breakdown-related genes(PNPLA2,LIPE,MGLL,ABHD5).This will result in a decrease in intracellular triglycerides and an increase in free fatty acids.At the same time,as cadmium exposure down-regulates fatty acid oxidation(CPT1A,CPT1 B,CPT2,ACADS)and mitochondrial biosynthesis(PPARGC1A)-related genes,excessive free fatty acids cannot be oxidized,resulting in ROS production,mitochondrial membrane potential changes and ATP content decreases,eventually causing endothelial dysfunction.Conclusion: Cadmium interferes with the fat metabolism of HMEC-1 cells,resulting in excessive accumulation of free fatty acids that are not oxidized into cellular energy,resulting in the production of reactive oxygen species and insufficient energy supply,ultimately leading to mitochondrial and endothelial dysfunction.This study describes the relationship between endothelial function and fat metabolism,and provides new insights into vascular endothelial injury induced by cadmium exposure.