Silent information regulator factor 2-related enzyme 1 (sirtuin 1, Sirt1) is a nicotinamide adenine dinucleotide-dependent deacetylase, which can deacetylate histone and non-histone proteins and other transcription factors, and is involved in the regulation of many physiological functions, including cell senescence, gene transcription, energy balance, and oxidative stress. Ischemia/hypoxia injury remains an unresolved and complicated situation in the diseases of ischemia stroke, heart failure, and coronary heart disease, especially among the old folks. Studies have demonstrated that aging could enhance the vulnerability of brain, heart, lung, liver, and kidney to ischemia/hypoxia injury and the susceptibility in old folks to ischemia/hypoxia injury might be associated with Sirt1. In this review, we mainly summarize the role of Sirt1 in modulating pathways against energy depletion and its involvement in oxidative stress, apoptosis, and inflammation under the condition of ischemia/hypoxia.
Unlike the role of autophagy in continuous hypoxia, the role of autophagy in intermittent hypoxia is unclear. To investigate whether autophagy is involved in intermittent hypoxia-caused hippocampal neuronal apoptosis, we studied the activity and action of autophagy in hippocampal neurons after exposure to intermittent hypoxia. We found the expression of autophagy-related proteins and the autolysosome formation were upregulated, and exposure to intermittent hypoxia led to a significant increase in light chain 3 (LC3) turnover and a decrease in SQSTM1/ p62 level in hippocampal neurons. Furthermore, accompanying autophagy activation, the level of hypoxia inducible factor-1α (HIF-1α) was increased. Conversely, inhibition of HIF-1α by chemical inhibitor or small interfering RNA (siRNA) downregulated the expression of autophagy-related proteins and blocked autophagy activation. We also found reactive oxygen species (ROS) increased after exposure to intermittent hypoxia, and inhibition of ROS by antioxidants decreased LC3-II expression. What's more, activation of autophagy by rapamycin exacerbated the apoptosis induced by intermittent hypoxia, whereas inhibition of autophagy by chloroquine or autophagyrelated genes siRNA (Beclin1, Atg5 and Atg7) ameliorated intermittent hypoxiainduced apoptosis. Additionally, X-linked inhibitor of apoptosis protein (XIAP), an apoptosis inhibitor protein, was decreased significantly after autophagy activation. Taken together, HIF-1α and ROS-mediated autophagy activation aggravated hippocampal neuronal apoptosis caused by intermittent hypoxia, and the decrease of XIAP might be one of the mechanisms of hippocampal neuronal apoptosis caused by autophagy activation.
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