title: Molecular hydrogen stabilizes atherosclerotic plaque in low-density lipoprotein receptor-knockout mice.
abstract: Hydrogen (H(2)) attenuates the development of atherosclerosis in mouse models. We aimed to examine the effects of H(2) on atherosclerotic plaque stability. Low-density lipoprotein receptor-knockout (LDLR(-/-)) mice fed an atherogenic diet were dosed daily with H(2) and/or simvastatin. In vitro studies were carried out in an oxidized-LDL (ox-LDL)-stimulated macrophage-derived foam cell model treated with or without H(2). H(2) or simvastatin significantly enhanced plaque stability by increasing levels of collagen, as well as reducing macrophage and lipid levels in plaques. The decreased numbers of dendritic cells and increased numbers of regulatory T cells in plaques further supported the stabilizing effect of H(2) or simvastatin. Moreover, H(2) treatment decreased serum ox-LDL level and apoptosis in plaques with concomitant inhibition of endoplasmic reticulum stress (ERS) and reduction of reactive oxygen species (ROS) accumulation in the aorta. In vitro, like the ERS inhibitor 4-phenylbutyric acid, H(2) inhibited ox-LDL- or tunicamycin (an ERS inducer)-induced ERS response and cell apoptosis. In addition, like the ROS scavenger N-acetylcysteine, H(2) inhibited ox-LDL- or Cu(2+) (an ROS inducer)-induced reduction in cell viability and increase in cellular ROS. Also, H(2) increased Nrf2 (NF-E2-related factor-2, an important factor in antioxidant signaling) activation and Nrf2 small interfering RNA abolished the protective effect of H(2) on ox-LDL-induced cellular ROS production. The inhibitory effects of H(2) on the apoptosis of macrophage-derived foam cells, which take effect by suppressing the activation of the ERS pathway and by activating the Nrf2 antioxidant pathway, might lead to an improvement in atherosclerotic plaque stability.
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, TaiShan Medical University, Tai'an 271000, China; Heart Center of TaiShan Medical University, Tai'an 271000, China. Electronic address: girl_sapphire@hotmail.com.
authors.forename: Guohua
authors.initials: G
authors.lastname: Song
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, TaiShan Medical University, Tai'an 271000, China; Heart Center of TaiShan Medical University, Tai'an 271000, China.
authors.forename: Chuanlong
authors.initials: C
authors.lastname: Zong
authors.affiliation: College of Basic Medical Sciences, TaiShan Medical University, Tai'an 271000, China.
authors.forename: Zhaoqiang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, TaiShan Medical University, Tai'an 271000, China; Heart Center of TaiShan Medical University, Tai'an 271000, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, TaiShan Medical University, Tai'an 271000, China; College of Basic Medical Sciences, TaiShan Medical University, Tai'an 271000, China.
authors.forename: Shutong
authors.initials: S
authors.lastname: Yao
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, TaiShan Medical University, Tai'an 271000, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Jiao
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, TaiShan Medical University, Tai'an 271000, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Tian
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, TaiShan Medical University, Tai'an 271000, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhai
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, TaiShan Medical University, Tai'an 271000, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, TaiShan Medical University, Tai'an 271000, China.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Tian
authors.affiliation: Hebei Collaborative Innovation Center for Cardiocerebrovascular Disease and Hebei Key Laboratory of Vascular Homeostasis, Shijiazhuang 050000, China.
authors.forename: Xiangjian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Heart Center of TaiShan Medical University, Tai'an 271000, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Diving Medicine, Second Military Medical University, Shanghai, China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Sun
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, TaiShan Medical University, Tai'an 271000, China; Heart Center of TaiShan Medical University, Tai'an 271000, China. Electronic address: shucunqin@hotmail.com.
authors.forename: Shucun
authors.initials: S
authors.lastname: Qin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D006859:Hydrogen / Q000008:administration & dosage / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D058226:Plaque, Atherosclerotic / Q000178:diet therapy / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D051131:Receptors, Oxidized LDL / Q000235:genetics / Q000378:metabolism*; D019821:Simvastatin / Q000008:administration & dosage
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D006859:Hydrogen; D019821:Simvastatin
keywords: Endoplasmic reticulum stress; Free radicals; Hydrogen; Macrophage apoptosis; NF-E2-related factor-2; Plaque stability