Cardiovascular Research Advance Access [Accepted Manuscript] published online on June 5, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp182
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Regulatory T cells ameliorate hyperhomocysteinemia-accelerated atherosclerosis in apoE-/- mice
Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, P. R. China
* To whom correspondence should be addressed: Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, Beijing 100191, P. R. China. Tele (Fax): +86 10 82801443, Email address: xwang{at}bjmu.edu.cn
Aims: Atherosclerosis is an inflammatory disease with T cell-driven immunoinflammatory responses contributing to disease initiation and progression. We investigated the potential role of regulatory T cells (Tregs) in hyperhomocysteinemia (HHcy)-accelerated atherosclerosis in apoE-/- mice.
Methods and results: ApoE-/- mice were fed normal mouse chow supplemented with or without a high level of homocysteine (Hcy) (1.8 g/L) in drinking water for 2, 4 and 6 weeks. Atherosclerotic lesion area was slightly increased at 2 weeks and substantially elevated at 4 and 6 weeks in HHcy apoE-/- mice. Cotransfer of normal Tregs significantly attenuated atherosclerotic lesion size and infiltration of T cells and macrophages into plaque. Furthermore, Treg cotransfer reversed HHcy-accelerated proliferation of T cells, -increased pro-inflammatory and -decreased anti-inflammatory cytokine secretion from activated splenic T cells. With a clinically relevant level of plasma Hcy, the proportion of Tregs and suppressive activity in splenic T cells were reduced in HHcy apoE-/- mice, which was associated with reduced mRNA and protein expression of Foxp3, a factor governing mouse Treg development and function. In addition, Hcy significantly attenuated the proportion and suppressive effects of Tregs in vitro.
Conclusions: HHcy suppresses the function of Tregs, which may be responsible for HHcy-accelerated atherosclerosis in apoE-/- mice
Time for primary review: 26 Days
a Cardiovascular Division, Kings College London BHF Centre, London SE5 9NU, UK