Abstract 1951: Histamine H1 Receptor is Required for Atherogenesis
Background and aims: Histamine is an endogenous amine that plays a critical role as a mediator of inflammation and allergic response. Most of the proinflammatory actions of histamine are mediated via H1 receptor (H1R). Although histamine affects numerous inflammatory processes, its relevance in atherogenesis remains unknown.
Methods: We used both a pharmacological and a genetic approach to modulate H1R- or H2 receptor (H2R) -signalling in a mouse model of atherosclerosis. Apolipoprotein E (ApoE)-deficient mice were treated for 12 weeks either with the H1R antagonist mepyramine, the H2R antagonist ranitidine, or placebo. In parallel, we compared H1R−/−ApoE−/− and H2R−/−ApoE−/− to ApoE single knockout mice after 12 weeks of stimulation with high cholesterol diet (Clinton-Cybulski diet, 1.25% cholesterol).
Results: ApoE-deficient animals treated with mepyramine, but not ranitidine, exhibited significantly reduced aortic plaque area compared with placebo-treated mice. Similarly, genetic deficiency of H1 receptor in ApoE−/− mice resulted in a 60% decrease in aortic plaque formation. Level of plasma lipids as well as permeability of the vessel wall was not affected by the absence of H1R. H1R-deficient animals showed significantly decreased levels of CCL5 and CD40 in the aorta. In parallel, atherosclerotic plaques of these animals revealed significantly decreased infiltration with macrophages and T-helper cells. Moreover, reduced blood lymphocyte number, spleen size, and decreased production of splenic Th1-specific cytokines (CCL5, IL-2, and IFNγ) were observed in the absence of H1R. Interestingly, bone marrow transplantation revealed, that the presence of H1R on bone marrow-derived cells is irrelevant for both atherosclerotic plaque formation and regulation of spleen size.
Conclusions: We conclude that blocking the H1 receptor leads to decreased atherogenesis due to indirect alteration of leukocyte function.