Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 87, Issue -, Pages 58-68Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2015.06.018
Keywords
Hydrogen; Plaque stability; Macrophage apoptosis; Endoplasmic reticulum stress; NF-E2-related factor-2; Free radicals
Funding
- National Natural Science Foundation of China [81200216, 81170785]
- Promotive Research Fund for Excellent Young and Middle-Aged Scientists of Shandong Province [BS2012YY034]
- Science and Technology Development Program of Shandong Province [2014GSF118081]
- Natural Science Foundation of Shandong Province [ZR2012HM034]
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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 oxiclized-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 denclritic 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 MRS) and reduction of reactive oxygen species (ROS) accumulation in the aorta. In vitro, like the ERS inhibitor 4-phenylbutyric acid, H-2 inhibited ox[DL- 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 Cu2+ (an ROS inducer)-induced reduction in cell viability and increase in cellular ROS. Also, H-2 increased Nrt2 (NF-E2-related factor-2, an important factor in antioxidant signaling) activation and Nrt2 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 macrophagederived 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. (C)2015 Published by Elsevier Inc.
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