title: Puerarin Suppresses Macrophage Activation via Antioxidant Mechanisms in a CaPO4-Induced Mouse Model of Aneurysm.
abstract: Aneurysm is characterized by balloon-like expansion of the arterial wall and eventual rupture of the aorta. The pathogenesis of aneurysm is associated with the degradation of matrix proteins by matrix metalloproteinases (MMPs) produced by activated macrophages. Although aneurysm is associated with significant mortality and morbidity, surgical intervention is the only proven treatment strategy. Therefore, development of therapeutic agents for aneurysm is greatly anticipated. Here, we demonstrated the protective effects of the major isoflavone puerarin, which is found in kudzu roots and vines. Aneurysms were surgically induced in ten-wk-old male mice using CaPO4. Subsequently, animals were intraperitoneally injected daily with puerarin at 2.5 mg/kg body weight or with vehicle alone for 2 wk. CaPO4-induced aneurysm was significantly suppressed by puerarin administration. In subsequent macrophage activation assays using Tumor necrosis factor (TNFα) and CaPO4crystals in vitro, puerarin decreased Mmp9 mRNA expression and secreted protein levels. Moreover, induction of IκB, ERK, and p38 phosphorylation by TNFα and CaPO4in macrophages was suppressed by puerarin treatments. Finally, puerarin attenuated reactive oxygen species production, following induction by TNFα and CaPO4. Taken together, the present data demonstrate that puerarin suppresses macrophage activation by inhibiting IκB, ERK, and p38 activity and reactive oxygen species production in a CaPO4-induced mouse model of aneurysm.
authors.affiliation: Division of Vascular Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health.
authors.forename: Teruyoshi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Moriyama
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kawamura
authors.forename: Dai
authors.initials: D
authors.lastname: Yamanouchi
mesh_terms: D000783:Aneurysm / Q000188:drug therapy*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002130:Calcium Phosphates; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007529:Isoflavones / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D018517:Plant Roots / Q000737:chemistry; D029908:Pueraria / Q000737:chemistry; D000067996:RAW 264.7 Cells; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002130:Calcium Phosphates; D020672:I-kappa B Proteins; D007529:Isoflavones; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; C020243:calcium phosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C033607:puerarin