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Novel function of histamine signaling in hyperlipidemia‐induced atherosclerosis: Histamine H 1 receptors protect and H 2 receptors accelerate atherosclerosis
Author(s) -
Yamada Sohsuke,
Wang KeYong,
Tanimoto Akihide,
Sasaguri Yasuyuki
Publication year - 2015
Publication title -
pathology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.73
H-Index - 74
eISSN - 1440-1827
pISSN - 1320-5463
DOI - 10.1111/pin.12246
Subject(s) - hyperlipidemia , apolipoprotein e , receptor , histamine receptor , histamine , inflammation , endocrinology , medicine , histamine h4 receptor , apolipoprotein b , cholesterol , scavenger receptor , knockout mouse , chemistry , lipoprotein , histamine h2 receptor , diabetes mellitus , disease , antagonist
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 H 1 and H 2 receptors ( HH 1 R , HH 2 R ) 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 HH 1 R / apoE ‐ DKO mice, but in HH 2 R / 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 , CD 36 and lectin‐like oxidized low‐density lipoprotein receptor 1 ( LOX ‐1), nuclear factor‐kappa B ( NF κ B ), 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 HH 2 R / apoE ‐ DKO mice. We hypothesize that histamine/ HH 1 R and HH 2 R 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, HH 2 R blockers, are a possible novel therapeutic target for hyperlipidemia‐induced atherosclerosis.