Ischemic Preconditioning and Clinical Scenarios

Srinivasan V. Narayanan; Kunjan R. Dave; Miguel A. Perez-Pinzon

Disclosures

Curr Opin Neurol. 2013;26(1):1-7. 

In This Article

Mitochondrial and Other Organelle Targets of Ischemic Preconditioning

As potent producers of ROS, mitochondria are key mediators of cell death following cerebral ischemia as well as in many neurological disorders, and therefore have become important targets for potential neuroprotective therapies.[33] In fact, mitochondria have been shown to play an important role in IPC-induced neuroprotection. IPC mitigates cerebral ischemia-induced neuronal death by several mechanisms, including prevention of decreased oxidative phosphorylation (OXPHOS) capacity, mitochondria-dependent cell death pathways, and ROS generation from the mitochondrial electron transport chain (ETC)[41–48] (Fig. 1). Because of their crucial role in IPC-induced neuroprotection, Dirnagl and Meisel[41] described mitochondria as 'gatekeepers of preconditioning'.

In addition, IPC appears to activate several pathways, which in turn modify mitochondrial proteins. In a previous study, we observed that within 1 h after IPC, the mitochondrial ATP-sensitive K+ (mitoK+ATP) channel was phosphorylated and activated by εPKC. This pathway led to the induction of ischemic-tolerance pathways, potentially by sublethal mitochondrial release of ROS.[49] Our group observed delayed IPC-mediated increases in synaptosomal εPKC levels, which contributed to improved mitochondrial OXPHOS capacity following an ordinarily lethal ischemic insult. The increased OXPHOS capacity was attributed to εPKC-induced posttranslational modifications of mitochondrial ETC components.[50]

IPC-induced improvement in brain mitochondrial OXPHOS capacity may also be because of IPC-mediated changes in OXPHOS gene expression. Several transcription factors have been shown to translocate to the nucleus following IPC, such as nuclear factor-kappa B (NF-[κ]B)[51] and cyclic-AMP response element-binding protein (CREB) pathways,[52] gene products of which can mediate IPC-induced neuroprotection; Liu et al.[53] identified 19 differentially expressed microRNAs (miRNAs) in the brains of hypoxia-preconditioned mice following middle cerebral artery occlusion. Bioinformatics analysis of the miRNA target genes of two conventional PKC (βIIPKC and γPKC)-interacting and one novel PKC (εPKC)-interacting proteins predicted involvement of major energy-generating pathways (glycolysis or gluconeogenesis, citrate cycle, and OXPHOS) in hypoxia preconditioning-induced neuroprotection. However, two similar studies suggested that IPC-induced alterations in miRNA expression pattern had no effect on mitochondrial OXPHOS.[54,55] Gene ontology analysis in another study identified mitochondria as one of the cellular organelles affected by IPC.[56] These studies suggest that IPC and hypoxic preconditioning differentially affect miRNA expression in relation to mitochondrial OXPHOS pathways. It appears that IPC positively regulates mitochondrial functions by directly affecting gene expression of specific mitochondrial proteins rather than by altering miRNA expression.

Following cerebral ischemia-induced excitotoxicity, altered neuronal calcium (Ca2+) buffering capacity plays a key role in potentiating neuronal cell death. In-vitro models of excitotoxicity demonstrated that a tolerance-inducing stimulus protected neurons from lethal excitotoxicity by increasing mitochondrial Ca2+ buffering capacity and by decreasing mitochondrial Ca2+ uptake.[57] Iijima et al.[58] reported that brief oxygen–glucose deprivation increased mitochondrial calcium loading capacity. These studies highlighted another important role for mitochondria in protecting cells against lethal ischemia-induced excitotoxicity.

Effects of Ischemic Preconditioning on Golgi Apparatus and Endoplasmic Reticulum

Other cellular organelles such as the Golgi apparatus also participate in cellular Ca2+ buffering. A previous study showed that IPC prevented lethal ischemia-induced suppression of secretory pathway Ca2+-ATPases (SPCA) in the Golgi apparatus by preventing hippocampal membrane lipid and protein oxidation. The same study also reported that IPC enhanced post-lethal ischemia expression of SPCA mRNA,[59] suggesting IPC may mediate neuroprotection through Golgi functions preservation. The role of endoplasmic reticulum (ER) in Ca2+ buffering following IPC is not known; however, earlier studies established that IPC reduced neuronal death after lethal ischemia by reducing ER stress.[60,61] A recent study demonstrated that IPC treatment reduced ischemic damage by increasing molecular chaperones levels through activation of autophagy, ultimately lowering ER stress during lethal ischemia.[62] Together with the ability of IPC to reduce oxidative damage, the previous studies suggest that IPC can reduce organelle stress, further contributing to ischemic tolerance.

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