Guangzhi Cong1, Ru Yan2, Hui Huang3, Kai Wang4, Ning Yan4, Ping Jin4, Na Zhang4, Jianjun Hou3, Dapeng Chen3, Shaobin Jia5. 1. Department of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750001, PR China; Institute of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, PR China. 2. Institute of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, PR China. 3. Heart Centre, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, PR China. 4. Department of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750001, PR China. 5. Institute of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, PR China; Heart Centre, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, PR China. Electronic address: jsbxn@163.com.
Abstract
AIMS: Hyperhomocysteinemia (Hhcy) is an independent risk factor of atherosclerosis and promotes unstable plaque formation. Epigenetic mechanisms play an important role in the pathogenesis of atherosclerosis induced by Hhcy. However, the exact mechanism is still undefined. Lesional apoptotic cells and necrotic core formation contribute greatly to the progression of plaque. The present study sought to determine whether modification of histone methylation is involved in macrophage apoptosis and unstable plaque formation in the condition of Hhcy. MATERIALS AND METHODS: The unstable plaque formation, lesional apoptotic cells and status of histone methylation were monitored in the aortas of Hhcy ApoE-/- mice induced by a high-methionine (HM) diet for 20weeks. Involvement of histone methylation in macrophage apoptosis and foam cell formation were assessed in macrophage Raw 264.7 cells after being challenged with homocysteine alone or in combination with the histone methylation inhibitor BIX 01294. KEY FINDINGS: The unstable plaque formation and lesion apoptotic cells are increased in ApoE-/- mice supplemented with high-methionine (HM), accompanied with a decreased expression of histone H3 lysine 9 dimethylation. Hhcy increases the apoptosis of macrophages and inhibits the histone H3 lysine 9 dimethylation, as well as the expression of histone methyltransferase G9a in vitro. Inhibition of histone methylation by BIX01294 enhances macrophage apoptosis and foam cell formation in vitro. SIGNIFICANCE: Our data suggest that Hhcy promotes the progression of atherosclerosis via macrophage apoptosis. Histone methylation might be involved in macrophage apoptosis and unstable plaque formation in methionine induced hyperhomocysteinemic ApoE-/- mice.
AIMS: Hyperhomocysteinemia (Hhcy) is an independent risk factor of atherosclerosis and promotes unstable plaque formation. Epigenetic mechanisms play an important role in the pathogenesis of atherosclerosis induced by Hhcy. However, the exact mechanism is still undefined. Lesional apoptotic cells and necrotic core formation contribute greatly to the progression of plaque. The present study sought to determine whether modification of histone methylation is involved in macrophage apoptosis and unstable plaque formation in the condition of Hhcy. MATERIALS AND METHODS: The unstable plaque formation, lesional apoptotic cells and status of histone methylation were monitored in the aortas of Hhcy ApoE-/- mice induced by a high-methionine (HM) diet for 20weeks. Involvement of histone methylation in macrophage apoptosis and foam cell formation were assessed in macrophage Raw 264.7 cells after being challenged with homocysteine alone or in combination with the histone methylation inhibitor BIX 01294. KEY FINDINGS: The unstable plaque formation and lesion apoptotic cells are increased in ApoE-/- mice supplemented with high-methionine (HM), accompanied with a decreased expression of histone H3 lysine 9 dimethylation. Hhcy increases the apoptosis of macrophages and inhibits the histone H3 lysine 9 dimethylation, as well as the expression of histone methyltransferase G9a in vitro. Inhibition of histone methylation by BIX01294 enhances macrophage apoptosis and foam cell formation in vitro. SIGNIFICANCE: Our data suggest that Hhcy promotes the progression of atherosclerosis via macrophage apoptosis. Histone methylation might be involved in macrophage apoptosis and unstable plaque formation in methionine induced hyperhomocysteinemic ApoE-/- mice.