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Hyperhomocystinemia(Hhcy) is an independent risk factor of atherosclerosis and promotes the unstable plaque formation. Epigenetic mechanisms play an important role in the pathogenesis of atherosclerosis induced by Hhcy. However, the exact mechanism still undefined. The present study sought to determine the hypothesis whether histone methylation modification is involved in macrophage apoptosis and unstable plaque formation in the condition of Hhcy.
ApoE-/-mice were supplemented with high-methionine (HM) diet for 20 weeks to induce Hhcy. Macrophage Raw 264.7 cells were challenged with homocysteine and histone inhibitor BIX 01294.
The hallmark of unstable plaque, lesion apoptotic cells are increased in ApoE-/-mice supplemented with high-methionine (HM), accompanied with a decrease expression of histone H3 lysine 9 dimethylation. Hcy increases the apoptosis of macrophage and inhibits the histone H3 lysine 9 dimethylation and the expression of histone methyltransferase G9a in vitro. Inhibition of histone methylation by BIX01294 enhances the macrophage apoptosis and foam cell formation in vitro.
Our data suggests that Hhcy promotes the progression of atherosclerosis via macrophage apoptosis. Histone methylation might involve in macrophage apoptosis and unstable plaque formation in methionine induced hyperhomocysteinemic ApoE-/- mice.