Xiaochen Ru1, Changbo Zheng2, Qiannan Zhao2, Hui-Yao Lan3, Yu Huang4, Song Wan5, Yasuo Mori6, Xiaoqiang Yao7. 1. Department of Basic Medical Sciences, Huzhou University Schools of Medicine and Nursing Sciences, Huzhou, China; Li Ka Shing Institute of Health Science and School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China. 2. Li Ka Shing Institute of Health Science and School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China. 3. Department of Medicine, The Chinese University of Hong Kong, Hong Kong, China. 4. Li Ka Shing Institute of Health Science and School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China. 5. Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China. 6. Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan. 7. Li Ka Shing Institute of Health Science and School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China. Electronic address: yao2068@cuhk.edu.hk.
Abstract
BACKGROUND: A hallmark of atherosclerosis is progressive intimal thickening (namely neointimal hyperplasia), which leads to occlusive vascular diseases. Over-production of reactive oxygen species (ROS) and alteration of Ca2+ signaling are among the key factors contributing to neointimal growth. In the present study, we investigated the role of TRPM2, a ROS-sensitive Ca2+ entry channel, in neointimal hyperplasia. METHODS AND RESULTS: Perivascular cuffs were used to induce neointimal hyperplasia in rat/mouse arteries. Immunostaining showed numerous TRPM2-positive smooth muscle cells in neointimal regions. ROS were over-produced and PCNA-positive proliferating cells were numerous in the neointimal regions. The neointimal hyperplasia was substantially reduced in Trpm2 knockout mice compared with wild-type mice. In the cultured rat/mouse aortic smooth muscle cells, H2O2 treatment was found to stimulate cell proliferation and migration. The effect of H2O2 was reduced by a TRPM2-specific blocking antibody TM2E3 or Trpm2 knockout. The signaling molecules downstream of TRPM2 were found to be Axl and Akt. CONCLUSIONS: These data suggest a critical functional role of TRPM2 in the progression of neointimal hyperplasia. The study also highlights the possibility of targeting TRPM2 as a potential therapeutic option for the treatment of occlusive vascular diseases.
BACKGROUND: A hallmark of atherosclerosis is progressive intimal thickening (namely neointimal hyperplasia), which leads to occlusive vascular diseases. Over-production of reactive oxygen species (ROS) and alteration of Ca2+ signaling are among the key factors contributing to neointimal growth. In the present study, we investigated the role of TRPM2, a ROS-sensitive Ca2+ entry channel, in neointimal hyperplasia. METHODS AND RESULTS: Perivascular cuffs were used to induce neointimal hyperplasia in rat/mouse arteries. Immunostaining showed numerous TRPM2-positive smooth muscle cells in neointimal regions. ROS were over-produced and PCNA-positive proliferating cells were numerous in the neointimal regions. The neointimal hyperplasia was substantially reduced in Trpm2 knockout mice compared with wild-type mice. In the cultured rat/mouse aortic smooth muscle cells, H2O2 treatment was found to stimulate cell proliferation and migration. The effect of H2O2 was reduced by a TRPM2-specific blocking antibody TM2E3 or Trpm2 knockout. The signaling molecules downstream of TRPM2 were found to be Axl and Akt. CONCLUSIONS: These data suggest a critical functional role of TRPM2 in the progression of neointimal hyperplasia. The study also highlights the possibility of targeting TRPM2 as a potential therapeutic option for the treatment of occlusive vascular diseases.