title: G004, a synthetic sulfonylurea compound, exerts anti-atherosclerosis effects by targeting SIRT1 in ApoE-/-mice.
abstract: Atherosclerosis attracts increasing global attention because of its morbidity and mortality. G004, as a synthetic sulfonylurea compound, has been confirmed to have anti-hyperglycaemia, anti-platelet and anti-thrombus effects. The aim of the present study was to investigate whether G004 suppress the onset and development of atherosclerosis and illuminate its probable mechanism of action. ApoE-/-mice that were fed a high-fat diet were randomly divided into five groups by weight; subsequently, they were treated with vehicle, G004, at different doses or atorvastatin once daily for 12weeks. Meanwhile, C57BL/6 mice with the same diet served as the normal controls. Then, the serum lipid profiles and histopathological damage to the liver, kidney, aortic arch and aortic root were analysed. The activation of endothelial nitric oxide synthase (eNOS) and levels of inflammatory markers were detected. Reverse cholesterol transport (RCT) was assessed in vivo by intraperitoneal injection of RAW264.7 cells that were radiolabelled with3H-cholesterol. The results indicated that G004 ameliorated the serum lipid accumulation, atherosclerotic lesions and liver steatosis. Additionally, this compound increased the expression of SIRT1 and eNOS as well as the phosphorylation and deacetylation of eNOS in the aorta, alleviating the inflammatory state. RCT was promoted in ApoE-/-mice, which was accompanied by increased expression of SIRT1/LXRα/ABCA1/G1 in the liver, and similar results appeared in the cholesterol efflux assay in RAW264.7 cells. The results provide a strong rationale for G004 to be an efficient anti-atherosclerosis agent that improved vascular endothelial dysfunction by stimulating SIRT1/eNOS and promoted RCT by stimulating SIRT1/LXRα/ABCA1/G1.
authors.affiliation: Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang Road, Nanjing 210009, China.
authors.forename: Lifen
authors.initials: L
authors.lastname: Qian
authors.affiliation: State Key Laboratory of Natural Medicine, School of Life Science and Technology, China Pharmaceutical University, 24 Tong Jia Xiang Road, Nanjing 210009, China.
authors.forename: Lingman
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang Road, Nanjing 210009, China. Electronic address: wwbsabc@163.com.
authors.forename: Guanzhong
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang Road, Nanjing 210009, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang Road, Nanjing 210009, China.
authors.forename: Huisheng
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang Road, Nanjing 210009, China.
authors.forename: Qidi
authors.initials: Q
authors.lastname: Ying
authors.affiliation: Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang Road, Nanjing 210009, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wen
authors.affiliation: Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang Road, Nanjing 210009, China. Electronic address: gaocongcpu@163.com.
authors.forename: Cong
authors.initials: C
authors.lastname: Gao
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000378:metabolism; D000107:Acetylation; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D020022:Genetic Predisposition to Disease; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D001057:Apolipoproteins E; D002317:Cardiovascular Agents; D002784:Cholesterol; D000071518:Liver X Receptors; D052250:Nitric Oxide Synthase Type III; D056564:Sirtuin 1; D013453:Sulfonylurea Compounds; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse; C000600709:G004 compound; C000605214:Nr1h3 protein, mouse; C496315:Nos3 protein, mouse; C470545:Sirt1 protein, mouse
keywords: Atherosclerosis; Endothelial nitric oxide synthase777; G004; Reverse cholesterol transport; SIRT1