Abstract
Although increased serum histamine levels and H1R expression in the plaque are seen in atherosclerosis, it is not known whether H1R activation is a causative factor in the development of the disease, or is a host defense response to atherogenic signals. In order to elucidate how pharmacological inhibition of histamine receptor 1 (H1R) signaling affects atherogenesis, we administered either cetirizine (1 and 4 mg/kg. b.w) or fexofenadine (10 and 40 mg/kg. b.w) to ApoE−/− mice maintained on a high fat diet for three months. Mice ingesting a low dose of cetirizine or fexofenadine had significantly higher plaque coverage in the aorta and cross-sectional lesion area at the aortic root. Surprisingly, the higher doses of cetirizine or fexofenadine did not enhance atherosclerotic lesion coverage over the controls. The low dose of fexofenadine, but not cetirizine, increased serum LDL cholesterol. Interestingly, the expression of iNOS and eNOS mRNA was increased in aortas of mice on high doses of cetirizine or fexofenadine. This may be a compensatory nitric oxide (NO)-mediated vasodilatory mechanism that accounts for the lack of increase in the progression of atherosclerosis. Although the administration of cetirizine did not alter blood pressure between the groups, there was a positive correlation between blood pressure and lesion/media ratio at the aortic root in mice receiving the low dose of cetirizine. However, this association was not observed in mice treated with the high dose of cetirizine or either doses of fexofenadine. The macrophages or T lymphocytes densities were not altered by low doses of H1-antihistamines, whereas, high doses decreased the number of macrophages but not T lymphocytes. The number of mast cells was decreased only in mice treated with low dose of fexofenadine. These results demonstrate that chronic ingestion of low therapeutic doses of cetirizine or fexofenadine enhance progression of atherosclerosis.
Highlights
Histamine, a major product of mast cells, regulates many vital physiological functions including vasodilation, allergic response and neurotransmission [1,2,3]
We have previously shown that histamine stimulates the production of both proatherogenic cytokines, such as IL-6, IL-8, and anti-atherogenic prostanoids, PGI2 and PGE2, in human coronary artery endothelial cells (HCAEC) through H1 receptor (H1R) activation [11,12,13,14]
The increase in atherogenesis by low doses of H1antihistamines is not associated with macrophage or T lymphocyte, but with a decrease in mast cell numbers in the lesions
Summary
A major product of mast cells, regulates many vital physiological functions including vasodilation, allergic response and neurotransmission [1,2,3]. The role of histamine and H1R in the pathophysiology of atherosclerosis has been studied, with special emphasis on its potential proatherogenic role [5,6]. In this regard, increased expression of H1R in human atheromas and elevated histamine content in atherosclerotic plaques in ApoE2/2 mice have been reported [6,7]. Previous reports show that first generation H1-antihistamines like chlorpheniramine [15], and mepyramine [16] reduce atherogenesis in pigs and ApoE2/2 mice, respectively. The objective of this study was to examine the effect of chronic ingestion of these H1-antihistamines on progression of atherosclerosis in ApoE2/2 mice
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