Blocking H1R signal aggravates atherosclerosis by promoting inflammation and foam cell formation

Abstract

Atherosclerosis (AS) is a chronic inflammatory arterial disease, in which abnormal lipid metabolism and foam cell formation play key roles. Histamine is a vital biogenic amine catalyzed by histidine decarboxylase (HDC) from L-histidine. Histamine H1 receptor (H₁R) antagonist is a commonly encountered anti-allergic agent in the clinic. However, the role and mechanism of H₁R in atherosclerosis have not been fully elucidated. Here, we explored the effect of H₁R on atherosclerosis using Apolipoprotein E-knockout (ApoE^-/-) mice with astemizole (AST, a long-acting H₁R antagonist) treatment. The results showed that AST increased atherosclerotic plaque area and hepatic lipid accumulation in mice. The result of microarray study identified a significant change of endothelial lipase (LIPG) in CD11b⁺ myeloid cells derived from HDC-knockout (HDC^-/-) mice compared to WT mice. Blocking H₁R promoted the formation of foam cells from bone marrow-derived macrophages (BMDMs) of mice by up-regulating p38 mitogen-activated protein kinase (p38 MAPK) and LIPG signaling pathway. Taken together, these findings demonstrate that blocking H₁R signal aggravates atherosclerosis by promoting abnormal lipid metabolism and macrophage-derived foam cell formation via p38 MAPK-LIPG signaling pathway. KEY MESSAGES: Blocking H₁R signal with AST aggravated atherosclerosis and increased hepatic lipid accumulation in high-fat diet (HFD)-fed ApoE^-/- mice. Blocking H₁R signal promoted macrophage-derived foam cell formation via p38 MAPK-LIPG signaling pathway.

Keywords: Atherosclerosis; H1R; LIPG; Macrophage-derived foam cell formation; P38 MAPK.