Novel function of histamine signaling in hyperlipidemia‐induced atherosclerosis: Histamine H 1 receptors protect and H 2 receptors accelerate atherosclerosis

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.