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

Area of Science:

• Cardiovascular Research
• Immunology
• Pharmacology

Background:

• Atherosclerosis (AS) is a chronic inflammatory arterial disease driven by abnormal lipid metabolism and foam cell formation.
• Histamine H1 receptor (H1R) antagonists are common anti-allergic drugs, but their role in AS remains unclear.
• Understanding H1R's mechanism in AS is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the effect of H1R blockade on atherosclerosis progression.
• To elucidate the underlying molecular mechanisms involving lipid metabolism and foam cell formation.

Main Methods:

• Utilized Apolipoprotein E-knockout (ApoE-/-) mice fed a high-fat diet (HFD).
• Administered astemizole (AST), a long-acting H1R antagonist, to assess its impact.
• Analyzed atherosclerotic plaque area, hepatic lipid accumulation, and macrophage foam cell formation.
• Investigated the role of p38 mitogen-activated protein kinase (p38 MAPK) and endothelial lipase (LIPG) signaling pathways.

Main Results:

• AST treatment significantly increased atherosclerotic plaque area and hepatic lipid accumulation in HFD-fed ApoE-/- mice.
• Microarray analysis revealed altered endothelial lipase (LIPG) expression in myeloid cells from histidine decarboxylase-knockout (HDC-/-) mice.
• H1R blockade promoted foam cell formation from bone marrow-derived macrophages (BMDMs) by upregulating p38 MAPK and LIPG signaling.

Conclusions:

• Blocking the H1R signal aggravates atherosclerosis.
• H1R antagonism promotes abnormal lipid metabolism and macrophage-derived foam cell formation.
• The p38 MAPK-LIPG signaling pathway is a key mechanism mediating the adverse effects of H1R blockade in atherosclerosis.