title: Pravastatin attenuates the action of the ETS domain-containing protein ELK1 to prevent atherosclerosis in apolipoprotein E-knockout mice via modulation of extracellular signal-regulated kinase 1/2 signal pathway.
abstract: Oxidative stress plays an important role in atherosclerosis, a vascular disease with high morbidity and mortality. The ETS domain-containing protein ELK1 is an oxidative stress-sensitive factor modulated by the extracellular signal-regulated kinase (ERK) 1/2 pathway. However, the role of ELK1 in the prevention of atherosclerosis by pravastatin remains unclear. In the present study, male apolipoprotein E-knockout (apoE-/-) mice fed a diet containing 1.25% cholesterol (w/w) were divided into two groups, one treated with pravastatin (80 mg/kg, 2-2.4 mg/mouse per day) for 8 weeks and the other not. Male C57BL/6J mice fed with a normal diet were used as a control group. Human umbilical vein endothelial cells (HUVEC) were cultured and treated with pravastatin (10 μmol/L) for 18 hours before testing for the presence or absence of 100 μmol/L H2O2(24 hours). Examination of pathological sections from mice aortas revealed that pravastatin treatment almost prevented atherosclerotic plaque formation. Pravastatin also inhibited increases in serum and aortic levels of oxidized low-density lipoprotein and aortic malondialdehyde levels and decreases in aortic reduced glutathione, and the activities of superoxide dismutase, catalase and glutathione peroxidase. H2O2-induced increases in reactive oxygen species in HUVECs were reversed by pravastatin by 48%. Pravastatin blocked the phosphorylation of ELK1 and ERK1/2 proteins and reduced mRNA levels of early growth response 1, a known atherogenic transcription factor upregulated by the ROS/ERK/ELK1 pathway, in mice. In conclusion, pravastatin attenuates the action of ELK1 induced by oxidative stress to prevent atherosclerosis, which is dependent partly on modulation of ERK1/2 signalling.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects*; D017035:Pravastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D050807:ets-Domain Protein Elk-1; D006861:Hydrogen Peroxide; D017035:Pravastatin
keywords: ETS domain-containing protein ELK1; atherosclerosis; early growth response 1; extracellular signal-regulated kinase1/2; oxidative stress; pravastatin