Histamine H1 Receptor Promotes Atherosclerotic Lesion Formation by Increasing Vascular Permeability for Low-Density Lipoproteins

Abstract

Objective-Enhanced endothelial permeability leading to intimal accumulation of low-density lipoproteins (LDL) stimulates the formation of atherosclerotic lesions. Histamine is known to increase vascular permeability. Whether this affects the formation of atherosclerotic lesions, however, remains elusive. Methods and Results-Apolipoprotein E-null (ApoE Ϫ/Ϫ ) mice treated with a histamine H1 receptor but not an H2 receptor antagonist developed 40% fewer atherosclerotic lesions in the aorta than placebo-treated controls. Similarly, genetic deletion of the H1 but not the H2 receptor resulted in a 60% reduction of lesions compared with ApoE Ϫ/Ϫ controls. The H1 receptor enhanced LDL permeability and lipid accumulation in the aorta, whereas plasma lipoprotein levels remained unaltered. 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 in vascular cells, whereas its presence in bone marrow-derived cells was irrelevant for plaque development. Mice expressing the H1 receptor exhibited higher levels of the chemokine (C-C motif) ligand 5 and higher numbers of macrophages and T-helper lymphocytes in plaques, higher numbers of circulating lymphocytes, and larger spleens.

Enhanced vascular permeability facilitates entry of plasma HDL and promotes macrophage-reverse cholesterol transport from skin in mice

“…Under these experimental conditions, the stimulatory effect of histamine on m-RCT appeared to be mediated mainly by the H1R, with the H2R exerting a small additive effect. Consistent with our fi ndings, activation of H1R, rather than H2R, has been found to enhance vascular permeability for endogenous LDL in cholesterol-fed apoE Ϫ / Ϫ mice without altering the plasma lipoprotein levels ( 34 ). It has been also shown that histamine increases the passage of LDL through monolayers of human arterial endothelial cells, having its peak at 2 h but rapidly decreasing to the control level within 4-6 h, and, moreover, that this effect can be blocked by the H1R antagonist pyrilamine, rather than by the H2R antagonist cimetidine ( 35 ).…”

Molecular Biology of Atherosclerosis

“…In contrast, no effect on atherosclerosis was seen with HRH2 KO or an H2 antagonist (ranitidine) (1515).…”

“…Ϫ/Ϫ bone marrow did not affect atherosclerosis (1515). In contrast, no effect on atherosclerosis was seen with HRH2 KO or an H2 antagonist (ranitidine) (1515).…”

“…This phase of endothelial activation is similar to the rapid, socalled, "type I" activation of endothelial cells by histamine. Incidentally, the H1 histamine receptor, a GPCR, appears to promote atherosclerosis by increasing vascular permeability for LDL (1515). Calcium channels are also involved in activation of endothelial cells by disturbed flow.…”

Histamine induces activation of protein kinase D that mediates tissue factor expression and activity in human aortic smooth muscle cells

“…The antagonists of histamine receptor 1 (H 1 ) abolish the effect of histamine and reduce the formation of intimal hyperplasia (14). Recently, it has been reported that histamine H 1 receptor promotes the development of atherosclerotic lesions by increasing vascular permeability for low-density lipoprotein (LDL) (19).…”