Lipoic Acid Antagonizes Paraquat Induced Vascular Endothelial Dysfunction And Mechanism Study

Paraquat(PQ)is a widely used herbicide in the agricultural fields.Paraquat can cause multiple organ damage when entering the human body,lacking effective antidote is the significant cause of high mortality in PQ poisoning.Here,we investigated the antagonistic effects of alpha lipoic acid(?-LA),a naturally existing antioxidant,on PQ toxicity in human microvascular endothelial cells(HMEC-1)and its underlying mechanisms.HMEC-1 cells were pretreated with 250,500 or 1000 ?M ?-LA for 3 h,followed by exposure to 1000 ?M PQ for 24 h.The cell viability,cell migration ability,nitric oxide(NO)levels,and expression of endothelial nitric oxide synthase(e NOS)and endothelin-1(ET-1)at the m RNA and protein levels were determined to indicate the changes in endothelial function.The levels of intracellular and mitochondrial reactive oxygen species(ROS)were measured as an indicator of oxidative stress,and the mitochondrial membrane potential(??m)and intracellular ATP content were assessed to evaluate the alteration in mitochondrial function.All the doses of 250,500 and 1000 ?M ?-LA significantly inhibited 1000 ?M PQ-induced cytotoxicity in HMEC-1 cells.?-LA pretreatment remarkably diminished the damage to cell migration ability,recovered the declined levels of the vasodilator factor nitric oxide(NO),elevated the expression level of endothelial nitric oxide synthases(e NOS),and inhibited the upregulated expression of vasoconstrictor factor Endothelin-1(ET-1).Moreover,?-LA pretreatment inhibited reactive oxygen species(ROS)generation,suppressed the damage to the mitochondrial membrane potential(??m)and mitigated the inhibition of adenosine triphosphate(ATP)production in HMEC-1 cells.These results suggested that the antagonistic mechanisms for ?-LA actions may be due to suppressing PQ-induced mitochondrial oxidative stress,preserving mitochondrial function and alleviating endothelial dysfunction.In summary,our present study provides novel insights into the protective effects and pharmacological potential of ?-LA against PQ toxicity in microvascular endothelial cells.