title: Histamine deficiency decreases atherosclerosis and inflammatory response in apolipoprotein E knockout mice independently of serum cholesterol level.
abstract: OBJECTIVE
  Histamine and histamine receptors are found in atherosclerotic lesions, and their signaling and subsequent proatherogenic or proinflammatory gene expression are involved in atherogenesis. In the present study, we generated apolipoprotein E (apoE) and histamine synthesizing histidine decarboxylase double knockout (DKO) mice on a C57BL/6J (wild-type mice) background to clarify the roles of histamine in atherosclerosis.
  
  
  RESULTS
  Wild-type, apoE knockout (KO), and DKO mice were fed a high-cholesterol diet to analyze hyperlipidemia-induced atherosclerosis. Compared with wild-type mice, apoE-KO mice showed increased expression of histamine and its receptors, corresponding to increased atherosclerotic lesion areas and expression of inflammatory regulators, such as nuclear factor-κB, scavenger receptors, inflammatory cytokines, and matrix metalloproteinases. Histamine deficiency after deletion of histidine decarboxylase reduced atherosclerotic areas and expression of a range of the inflammation regulatory genes, but serum cholesterol levels of DKO mice were higher than those of apoE-KO mice.
  
  
  CONCLUSIONS
  These results indicate that histamine is involved in the development of atherosclerosis in apoE-KO mice by regulating gene expression of inflammatory modulators, an action that appears to be independent of serum cholesterol levels. In addition to acute inflammatory response, histamine participates in chronic inflammation, such as hyperlipidemia-induced atherosclerosis, and might be a novel therapeutic target for the treatment of atherosclerosis.
authors.affiliation: Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Ke-Yong
authors.initials: KY
authors.lastname: Wang
authors.forename: Akihide
authors.initials: A
authors.lastname: Tanimoto
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.forename: Sohsuke
authors.initials: S
authors.lastname: Yamada
authors.forename: Shohei
authors.initials: S
authors.lastname: Shimajiri
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Murata
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
authors.forename: Seiya
authors.initials: S
authors.lastname: Kato
authors.forename: Teruo
authors.initials: T
authors.lastname: Watanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohtsu
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Hirano
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Kohno
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sasaguri
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood*; D002791:Cholesterol, Dietary; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005838:Genotype; D006632:Histamine / Q000172:deficiency*; D006640:Histidine Decarboxylase / Q000172:deficiency / Q000235:genetics; D006949:Hyperlipidemias / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D011968:Receptors, Histamine / Q000235:genetics / Q000378:metabolism; D051116:Receptors, Scavenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D011968:Receptors, Histamine; D051116:Receptors, Scavenger; D006632:Histamine; D002784:Cholesterol; D020782:Matrix Metalloproteinases; D006640:Histidine Decarboxylase