title: Novel function of histamine signaling in hyperlipidemia-induced atherosclerosis: Histamine H1 receptors protect and H2 receptors accelerate atherosclerosis.
abstract: Histamine is not only essential for acute inflammatory reactions, but it also participates in a chronic inflammatory disorder. We generated apolipoprotein E (apoE) and histamine receptors (HHRs), including the major H1 and H2 receptors (HH1R, HH2R) double knockout mice (DKO) to clarify the role of HHRs in hyperlipidemia-induced atherosclerosis, in which apoE-KO and DKO mice were fed a high cholesterol diet. We found that pronounced hyperlipidemia-induced atherosclerotic progression occurred in HH1R/apoE-DKO mice, but in HH2R/apoE-DKO mice less atherosclerosis, despite pro-atherogenic serum cholesterol levels compared with apoE-KO mice. Furthermore, the increased expressions of scavenger receptors (SRs), such as SR-A, CD36 and lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), nuclear factor-kappa B (NFκB), monocyte chemoattractant protein (MCP-1), matrix metalloproteinases (MMPs) or liver X receptor (LXR)-related inflammatory signaling factors, were consistent with the pro-atherogenic phenotype of HH2R/apoE-DKO mice. We hypothesize that histamine/HH1R and HH2R signaling has conflicting innate functions, inflammatory/atherogenic and anti-inflammatory/anti-atherogenic actions, and that there are innate links between histamine signaling and hyperlipidemia-induced atherosclerosis, independently of serum cholesterol metabolism. Specific histamine signaling blockers, in particular, HH2R blockers, are a possible novel therapeutic target for hyperlipidemia-induced atherosclerosis.
authors.affiliation: Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu.
authors.forename: Sohsuke
authors.initials: S
authors.lastname: Yamada
authors.forename: Ke-Yong
authors.initials: KY
authors.lastname: Wang
authors.forename: Akihide
authors.initials: A
authors.lastname: Tanimoto
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sasaguri
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism*; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006632:Histamine / Q000378:metabolism*; D006949:Hyperlipidemias / Q000150:complications; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D011970:Receptors, Histamine H2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D006632:Histamine
keywords: histamine; histamine H1 receptor (HH1R); histamine H2 receptor (HH2R); hyperlipidemia-induced atherosclerosis; inflammatory factors; scavenger receptor (SR)