Abstract 5198: Histamine H1 Receptor Promotes Atherosclerotic Lesion Formation by Increasing Vascular Permeability for Low Density Lipoproteins
Enhanced endothelial permeability with intimal accumulation of low density lipoproteins (LDL) stimulates the formation of atherosclerotic lesions. Histamine is known to increase vascular permeability. Here we demonstrate that ApoE−/− mice treated with a histamine H1, but not H2 receptor antagonist developed 40% less atherosclerotic lesions in the aorta than placebo treated controls. Similarly, genetic deletion of the H1, but not H2 receptor resulted in 60% reduction of lesions compared to ApoE−/− controls. The H1 receptor enhanced permeability for LDL and lipid accumulation in aorta, whereas plasma lipoprotein levels remained unaffected. In contrast, the H1 receptor did not affect proliferation and migration of vascular smooth muscle cells. Bone marrow transplantation confirmed that the formation of atherosclerotic lesions depended on the H1 receptor on vascular cells, while its presence on bone marrow-derived cells was irrelevant for plaque development. Mice expressing the H1 receptor exhibited higher levels of the chemokine CCL5 and higher numbers of macrophages and lymphocytes in plaques, higher numbers of circulating lymphocytes, and larger spleens. These observations indicate that H1, but not H2 receptor activation drives the formation of atherosclerotic lesions through an increased vascular permeability for LDL, which is associated with an enhanced secondary aortic and systemic inflammation.