Novel function of histamine signaling in hyperlipidemia-induced atherosclerosis: Histamine H1 receptors protect and H2 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 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.
['Yamada|Sohsuke|S|', 'Wang|Ke-Yong|KY|', 'Tanimoto|Akihide|A|', 'Sasaguri|Yasuyuki|Y|']
D000818:Animals D050197:Atherosclerosis D015153:Blotting, Western D002851:Chromatography, High Pressure Liquid D004195:Disease Models, Animal D004797:Enzyme-Linked Immunosorbent Assay D006632:Histamine D006949:Hyperlipidemias D007150:Immunohistochemistry D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D060888:Real-Time Polymerase Chain Reaction D011969:Receptors, Histamine H1 D011970:Receptors, Histamine H2 D015398:Signal Transduction
histamine hyperlipidemia-induced atherosclerosis scavenger receptor (SR) histamine H1 receptor (HH1R) histamine H2 receptor (HH2R) inflammatory factors