Ezetimibe Protects Endothelial Cells against Oxidative Stress through Akt/GSK-3β Pathway / 华中科技大学学报（医学）（英德文版）

Ezetimibe was reported to pharmacologically defend against oxidative stress.This study was designed to investigate whether ezetimibe can protect against the oxidative stress induced by oxidized low-density lipoprotein (oxLDL) in vitro and the underlying mechanism.Human umbilical vein endothelial cells (HUVECs) were pretreated with ezetimibe and then exposed to oxLDL for 24 h.TUNEL assay and detection for the protein levels of cleaved caspase-3,Bcl-xl and Bcl-2 were employed to assess the oxLDL-induced endothelial apoptosis.Intracellular reactive oxygen species (ROS) generation was evaluated by measuring dichlorofluorescein (DCF) fluorescence.The activities of endothelial antioxidant enzymes [superoxide dismutase (SOD) and catalase] were tested via an enzymatic assay.The mitochondrial membrane potential (MMP) was monitored by flow cytometry using JC-1 staining.Phosphorylation levels of glycogen synthase kinase-3β (p-GSK-3β) and Akt (p-Akt),as well as total GSK-3β and Akt were determined by Western blotting.The results showed that ezetimibe treatment inhibited HUVECs apoptosis,intracellular ROS production,and enhanced antioxidant enzyme activities elicited by oxLDL.HUVECs exposed to oxLDL alone had reduced mitochondrial function,while ezetimibe pre-intervention could significantly rescue the MMP.Furthermore,the protein levels of p-GSK-3β and p-Akt in ezetimibe-pretreated HUVECs were markedly increased as compared with those in oxLDL-induced HUVECs.However,no significant effect on total GSK-3β and Akt was found in ezetimibe-pretreated HUVECs.Taken together,it was concluded that ezetimibe protects against oxLDL-induced oxidative stress through restoring the MMP,which may be mediated by Akt-dependent GSK-3β phosphorylation.

Ezetimibe Protects Endothelial Cells against Oxidative Stress through Akt/GSK-3β Pathway / 华中科技大学学报（医学）（英德文版）

Ezetimibe was reported to pharmacologically defend against oxidative stress.This study was designed to investigate whether ezetimibe can protect against the oxidative stress induced by oxidized low-density lipoprotein (oxLDL) in vitro and the underlying mechanism.Human umbilical vein endothelial cells (HUVECs) were pretreated with ezetimibe and then exposed to oxLDL for 24 h.TUNEL assay and detection for the protein levels of cleaved caspase-3,Bcl-xl and Bcl-2 were employed to assess the oxLDL-induced endothelial apoptosis.Intracellular reactive oxygen species (ROS) generation was evaluated by measuring dichlorofluorescein (DCF) fluorescence.The activities of endothelial antioxidant enzymes [superoxide dismutase (SOD) and catalase] were tested via an enzymatic assay.The mitochondrial membrane potential (MMP) was monitored by flow cytometry using JC-1 staining.Phosphorylation levels of glycogen synthase kinase-3β (p-GSK-3β) and Akt (p-Akt),as well as total GSK-3β and Akt were determined by Western blotting.The results showed that ezetimibe treatment inhibited HUVECs apoptosis,intracellular ROS production,and enhanced antioxidant enzyme activities elicited by oxLDL.HUVECs exposed to oxLDL alone had reduced mitochondrial function,while ezetimibe pre-intervention could significantly rescue the MMP.Furthermore,the protein levels of p-GSK-3β and p-Akt in ezetimibe-pretreated HUVECs were markedly increased as compared with those in oxLDL-induced HUVECs.However,no significant effect on total GSK-3β and Akt was found in ezetimibe-pretreated HUVECs.Taken together,it was concluded that ezetimibe protects against oxLDL-induced oxidative stress through restoring the MMP,which may be mediated by Akt-dependent GSK-3β phosphorylation.

Angiotensinogen polymorphisms and acquired atrial fibrillation in Chinese.

Genetic predisposition may be underlying the prevalence of acquired atrial fibrillation (AF). We investigated the association between polymorphism in angiotensinogen (AGT) and angiotensin-converting enzyme gene and risk of acquired AF in a pair-matched case-control study conducted in Chinese Hans. We selected 9 single nucleotide polymorphisms (SNPs) in the AGT gene and 3 SNPs in the angiotensin-converting enzyme gene using a tagging-SNP strategy. We observed significant association between tagging-SNP rs699 (M235T), located in exon 2 of the AGT gene, and AF. The AA genotype of rs699 increased the risk of AF by 70% (95% confidence interval, 1.01-2.85; P = .044) under a recessive model (AA vs AG + GG). The significance remained after controlling for covariates age, smoking, body mass index, hypertension, diabetes, and left atrial dimension, with an increased risk of AF by 90% (95% confidence interval, 1.04-3.46; P = .036). We provide evidence that polymorphism in AGT gene may confer predisposition to acquired atrial fibrillation in Chinese Hans.

Genetic polymorphism of KCNH2 confers predisposition of acquired atrial fibrillation in Chinese.

INTRODUCTION: Nonfamiliar atrial fibrillation (AF) is usually associated with acquired structural heart disease, including valvular heart disease, coronary artery disease, and hypertension. Suggestive evidence indicates that these forms of acquired AF are more likely to occur in individuals with a genetic predisposition. We investigated the effect of the potassium channel voltage-gated subfamily member 2 (KCNH2) gene on the prevalence of acquired AF in a Chinese population. METHODS: In a pair-matched, hospital-based case control study (297 vs 297) conducted in Chinese Hans, we investigated 4 tagging single nucleotide polymorphisms (tSNPs), rs1805120, rs1036145, rs3807375, and rs2968857 in the KCNH2 gene, and determined their association with AF acquired from structural heart diseases. RESULTS: We did not observe the association of rs1036145, rs3807375, and rs2968857 with AF. However, we determined that the tSNP, rs1805120, in exon 6 confers the risk of AF in Chinese Hans. Both genotype and allele frequencies of rs1805120 were distributed differently in cases and controls (P = 0.0289 and P = 0.0172, respectively). The most significant association was observed under a recessive model for the minor GG genotype with a 1.45-fold risk of developing AF (95% confidence interval 1.09-1.93, P = 0.012). The significance remained after controlling for the covariates of age, smoking, BMI, hypertension, and diabetes. CONCLUSION: We report a new genetic variation (rs1805120) in the KCNH2 gene that predisposes Chinese Han individuals to the risk of acquired AF. Further genetic and functional studies are required to identify the etiological variants in linkage disequilibrium with this polymorphism.