Abstract
Autophagy disruption leads to neuronal damage in hypoxic–ischemic brain injury. Rab7, a member of the Rab GTPase superfamily, has a unique role in the regulation of autophagy. Hypoxic preconditioning (HPC) provides neuroprotection against transient global cerebral ischemia (tGCI). However, the underlying mechanisms remain poorly understood. Thus, the current study explored the potential molecular mechanism of the neuroprotective effect of HPC by investigating how Rab7 mediates autophagosome (AP) maturation after tGCI in adult rats. We found that HPC attenuated AP accumulation in the hippocampal CA1 region after tGCI via restoration of autophagic flux. We also confirmed that this HPC-induced neuroprotection was not caused by the increase in lysosomes or the improvement of lysosomal function after tGCI. Electron microscopic analysis then revealed an increase in autolysosomes in CA1 neurons of HPC rats. Moreover, the inhibition of autophagosome-lysosome fusion by chloroquine significantly aggravated neuronal death in CA1, indicating that AP maturation contributes to HPC-induced neuroprotection against neuronal injury after tGCI. Furthermore, the activation of Rab7 was found to be involved in the neuroprotective effect of AP maturation after HPC. At last, the knockdown of ultraviolet radiation resistance-associated gene (UVRAG) in vivo disrupted the interaction between Vps16 and Rab7, attenuated the activation of Rab7, interrupted autophagic flux, and ultimately abrogated the HPC-induced neuroprotection against tGCI. Our results indicated that AP maturation was enhanced by the activation of Rab7 via UVRAG-Vps16 interaction, which further demonstrated the potential neuroprotective role of Rab7 in HPC against tGCI-induced neuronal injury in adult rats.
Highlights
Transient global cerebral ischemia can be caused by drowning, cardiac arrest or cardiopulmonary bypass surgery, leading to delayed neuronal death in the hippocampal CA1 subregion
We further confirmed that the light chain 3 (LC3)-II/LC3-I ratio in CA1 increased in time-dependent manner after Transient global cerebral ischemia (tGCI), and this increase was reversed by hypoxia preconditioning (HPC) (Figure 1C)
Several studies have demonstrated that cardioprotection elicited by Ischemic preconditioning (IPC) was mediated via upregulation of autophagy.[31,32]
Summary
Transient global cerebral ischemia (tGCI) can be caused by drowning, cardiac arrest or cardiopulmonary bypass surgery, leading to delayed neuronal death in the hippocampal CA1 subregion. Autophagy is a process that degrades intracellular organelles and long-lived cytosolic proteins to maintain cell homeostasis. It includes four stages: initiation, elongation, maturation and degradation.[3,4] Autophagy is initiated by forming a doublemembraned compartment known as an autophagosome (AP). Mutations in Rab[7], as well as its abnormal expression and activity, might be associated with neurodegenerative diseases, lipid storage disorders and heart diseases.[16,17,18] In addition, the downregulation of Rab[7] induced by myocardial ischemia would lead to disturbance of AP maturation.[19] little is known about the roles and the molecular mechanisms of Rab[7] in AP maturation after cerebral ischemia. Collins et al.[23] reported that the
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