title: 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.
  
  
  RESULTS
  Apolipoprotein E-null (ApoE(-/-)) 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(-/-) 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.
  
  
  CONCLUSIONS
  These data 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. These data open novel perspectives for the prevention and treatment of atherosclerotic vascular disease.
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich, Switzerland.
authors.forename: Izabela
authors.initials: I
authors.lastname: Rozenberg
authors.forename: Susanna H M
authors.initials: SH
authors.lastname: Sluka
authors.forename: Lucia
authors.initials: L
authors.lastname: Rohrer
authors.forename: Janin
authors.initials: J
authors.lastname: Hofmann
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
authors.forename: Alexander
authors.initials: A
authors.lastname: Akhmedov
authors.forename: Jorge
authors.initials: J
authors.lastname: Soliz
authors.forename: Pavani
authors.initials: P
authors.lastname: Mocharla
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.forename: Pål
authors.initials: P
authors.lastname: Johansen
authors.forename: Jan
authors.initials: J
authors.lastname: Steffel
authors.forename: Takeshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Felix C
authors.initials: FC
authors.lastname: Tanner
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001025:Aortitis / Q000276:immunology / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016026:Bone Marrow Transplantation; D002199:Capillary Permeability / Q000187:drug effects; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006632:Histamine / Q000378:metabolism*; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D011969:Receptors, Histamine H1 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011970:Receptors, Histamine H2 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D006632:Histamine