9/9/2023 0 Comments Gylt sarah mangan![]() ![]() To assess whether PHDs play a role in brain ischemia, we performed a permanent middle cerebral artery occlusion (pMCAO) in previously generated PHD1 deficient (PHD1 −/−) and PHD3 deficient (PHD3 −/−) mice. PHD1 −/− mice are protected against permanent brain ischemia These findings not only identify a novel therapeutic target for ischemic stroke but also provide novel insights into the link between oxygen sensors, metabolism and neuroprotection. Of therapeutic importance, silencing of PHD1 by intracerebroventricular delivery of antisense oligonucleotides protected against brain ischemia. This enabled PHD1 −/− neurons to maintain redox homeostasis during ischemic events. In contrast to the metabolic phenotype in PHD1 −/− muscle ( Aragones et al., 2008), PHD1 −/− neurons shunted more glucose into the anti-oxidant pentose phosphate pathway (PPP), while reducing glycolytic flux. Our results show that deletion of PHD1 largely prevented brain ischemic injury after stroke induction. In this study, we examined the role of the oxygen sensor PHD1 in brain ischemia after stroke induction, and focused on its possible role in controlling neuronal metabolism in this process. However, it remains unknown if PHDs control metabolism of neurons in a similar manner, and whether HIFs are their primary target in this process. ![]() For instance, loss of PHD1 makes the muscle and liver ischemia-tolerant by shifting mitochondrial metabolism towards anaerobic glycolysis ( Aragones et al., 2008 Schneider et al., 2009). In general, through stabilization of HIFs, PHD inhibition induces a shift from oxidative to anaerobic metabolism, thereby enhancing glycolysis at the expense of glucose oxidation ( Aragones et al., 2009). ![]() Moreover, PHDs have been implicated in instructing various metabolic adaptations, but primarily in cell types other than neurons. Surprisingly little is known about the functions of the PHDs in the brain. Thus, when oxygen levels drop and PHDs lose their activity, HIFs and other target proteins accumulate ( Quaegebeur and Carmeliet, 2010 Semenza, 2011). When oxygen is present, PHD-mediated hydroxylation targets proteins for proteasomal degradation. The transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α are the best characterized PHD targets, yet many other targets continue to be identified ( Wong et al., 2013). Since their hydroxylation of target proteins is oxygen-dependent, PHDs act as oxygen sensors. Prolyl hydroxylase domain proteins (PHD1-3) are master regulators of the response to hypoxia ( Quaegebeur and Carmeliet, 2010 Semenza, 2011). Nonetheless, despite progress in preclinical studies, there are no clinically approved neuroprotective treatments. This salvageable tissue is the target of reperfusion and neuroprotective strategies ( Moskowitz et al., 2010). It suffers only moderate blood flow reduction, and remains viable during a limited period of time before a cascade of deleterious events threatens the energy and redox homeostasis, ultimately causing ischemic neuronal death ( Lo et al., 2003 Moskowitz et al., 2010). A main target of such therapies is the ischemic penumbra, a region surrounding a core of necrotic tissue. This is nonetheless an important question, since ischemic stroke, resulting from acute arterial occlusion, is currently the fourth leading cause of death and the most common reason of severe disability, for which there is a large unmet medical need for efficient therapies. Apart from some studies ( Cui et al., 2006 Fang et al., 2014 Knight et al., 2014 Morais et al., 2014 Rodriguez-Rodriguez et al., 2013 Tufi et al., 2014), it remains largely unknown if neuronal metabolism is a target to promote neuroprotection. In fact, there is even ongoing debate about the precise metabolism of neurons in baseline conditions ( Belanger et al., 2011 Jolivet et al., 2010 Mangia et al., 2011). However, in contrast to the knowledge on how cancer cells and some other non-transformed cell types (immune cells, endothelial cells, etc.) alter their metabolism in disease ( DeBerardinis and Cheng, 2010 Ghesquiere et al., 2014 Schulze and Harris, 2012 Vander Heiden et al., 2009), it remains poorly understood how neurons adapt their metabolism upon ischemic neuronal injury. It is well established that this organ relies primarily on oxidative glucose metabolism for the production of energy ( Howarth et al., 2012 Mergenthaler et al., 2013). The brain is the largest consumer of oxygen and glucose in the human body. ![]()
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