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Chronic Ingestion of H1-Antihistamines Increase Progression of Atherosclerosis in Apolipoprotein E-/- Mice
Raveendra, Vineesh V. Smith, Donald D. Tan, Xiaoyu Sweeney, Matthew E. Reed, Gregory A. Flynn, Colleen A. Tawfik, Ossama W. Milne, Ginger Dileepan, Kottarappat N.
Raveendra, Vineesh V.
Smith, Donald D.
Tan, Xiaoyu
Sweeney, Matthew E.
Reed, Gregory A.
Flynn, Colleen A.
Tawfik, Ossama W.
Milne, Ginger
Dileepan, Kottarappat N.
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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 ApoE2/2 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.
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This is an Open Access article distributed under the terms of the Open Access Policy.
Date
2014-07-14
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Public Library of Science
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: Raveendran VV, Smith DD, Tan X, Sweeney ME, Reed GA, et al. (2014) Chronic Ingestion of H1-Antihistamines Increase Progression of Atherosclerosis in Apolipoprotein E-/- Mice. PLoS ONE 9(7): e102165. http://dx.doi.org/10.1371/journal.pone.0102165