title: I4, a synthetic anti-diabetes agent, attenuates atherosclerosis through its lipid-lowering, anti-inflammatory and anti-apoptosis properties.
abstract: Here, we investigated whether I4, which was initially developed as a hypoglycemic agent, possesses anti-atherosclerotic activity and attempted to elucidate the probable mechanism of action underlying this activity. ApoE-/-mice were fed a Western diet and simultaneously administered I4, glimepiride, or pioglitazone once daily for 12 weeks, and the atherosclerotic vascular lesions, lipid content, and expression levels of LOX-1, ICAM-1, VCAM-1 and Bax/Bcl-2 in mouse aortas were assessed. RAW264.7 macrophage-derived foam cells were obtained via ox-LDL stimulation to investigate the lipid-lowering, anti-atherosclerotic inflammation and anti-apoptotic effect of I4. The data indicated that I4significantly decreased the lipid accumulation in the circulation and tissue, especially for TG and FFA levels (p < 0.05 vs model group), alleviating the arterial and liver lesions induced by lipotoxicity. Its lipid-reducing effects may due to LOX-1and CD36 expression suppression. I4, at doses of 20 mg/kg and 10 mg/kg, significantly decreased serum IL-6, IL-1β, and TNF-α production and suppressed the expression of p-ERK, p-p38, VCAM-1 and ICAM-1 protein. I4attenuated atherosclerotic inflammation by blocking NF-κB nuclear translocation, suppressing MAPK/NF-κB signaling pathway and diminishing NF-κB-VCAM-1 promoter region binding. Additionally, I4suppressed p-p53 and cleaved-caspase-3 expression to inhibit foam cell apoptosis induced by ox-LDL uptake. Overall, I4exerts potent inhibitory effects on atherosclerosis onset and development.
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Lingman
authors.initials: L
authors.lastname: Ma
authors.affiliation: School of Pharmacy, Department of Pharmacology, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Lifen
authors.initials: L
authors.lastname: Qian
authors.affiliation: School of Pharmacy, Department of Pharmacology, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Qidi
authors.initials: Q
authors.lastname: Ying
authors.affiliation: School of Pharmacy, Department of Pharmacology, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: cl_zhou@cpu.edu.cn.
authors.forename: Changlin
authors.initials: C
authors.lastname: Zhou
authors.affiliation: School of Pharmacy, Department of Pharmacology, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: wwbsabc@163.com.
authors.forename: Guanzhong
authors.initials: G
authors.lastname: Wu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D018955:CD36 Antigens / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000150:complications / Q000188:drug therapy; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000067996:RAW 264.7 Cells; D051127:Scavenger Receptors, Class E / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013453:Sulfonylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D018955:CD36 Antigens; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D016328:NF-kappa B; C495138:Olr1 protein, mouse; D051127:Scavenger Receptors, Class E; D013453:Sulfonylurea Compounds; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D020928:Mitogen-Activated Protein Kinases
keywords: Anti-apoptosis; Atherosclerotic inflammation; I4; Lipid deposition; NF-κB activation