Loss of miR-29b following Acute Ischemic Stroke Contributes to Neural Cell Death and Infarct Size

Abstract

Glutathione depletion and 12-lipoxygenase-dependent metabolism of arachidonic acid are known to be implicated in neurodegeneration associated with acute ischemic stroke. The objective of this study was to investigate the significance of miR-29 in neurodegeneration associated with acute ischemic stroke. Neural cell death caused by arachidonic acid insult of glutathionedeficient cells was preceded by a 12-lipoxygenase-dependent loss of miR-29b. Delivery of miR-29b mimic to blunt such loss was neuroprotective. miR-29b inhibition potentiated such neural cell death. 12-Lipoxygenase knockdown and inhibitors attenuated the loss of miR-29b in challenged cells. In vivo, stroke caused by middle-cerebral artery occlusion was followed by higher 12-lipoxygenase activity and loss of miR-29b as detected in laser-captured infarct site tissue. 12-Lipoxygenase knockout mice demonstrated protection against such miR loss. miR-29b gene delivery markedly attenuated stroke-induced brain lesion. Oral supplementation of a-tocotrienol, a vitamin E 12-lipoxygenase inhibitor, rescued stroke-induced loss of miR-29b and minimized lesion size. This work provides the first evidence demonstrating that loss of miR-29b at the infarct site is a key contributor to stroke lesion. Such loss is contributed by activity of the 12-lipoxygenase pathway providing maiden evidence linking arachidonic acid metabolism to miR-dependent mechanisms in stroke.

MicroRNA-29b is a Therapeutic Target in Cerebral Ischemia Associated with Aquaporin 4

“…Delivery of miR-29b mimic reduced 50% of strokeinduced brain lesion after 48 hours transient cerebral ischemia. 13 We found that miR-29b overexpression reduced brain infarct volume, alleviated brain edema, and attenuated the BBB damage. However, Shi et al 33 found that upregulated miR-29b promoted neuronal cell death after ischemic brain injury.…”

“…32 The loss of miR-29b in the infarct region contributed to the injury of focally ischemic brain. 13 Another study reported that the miR-29b increased after cerebral ischemia. However, this study measured miR-29b in whole brain after stroke, which might mask changes in different focal region.…”

“…12 The level of miR-29b decreased after acute ischemic stroke, contributing to neural cell death and brain infarction. 13 With the help of bioinformatic-based databases 14 and published reports, 15,16 we found that AQP4 might be a potential direct target of miR-29b. The present study validated for the first time that indeed miR-29b regulated AQP4 level.…”

AGO CLIP reveals an activated network for acute regulation of brain glutamate homeostasis after ischemic stroke

“…http://dx.doi.org/10.1101/245928 doi: bioRxiv preprint first posted online Jan. 10, 2018; REST, activated by global ischemia. Over-expression of individual miR-29 family members has shown to improve stroke outcome in animal models by reducing infarct volume (Pandi et al, 2013, Wang et al, 2015, Khanna et al, 2013, and enhance post-stroke sensorimotor function (Khanna et al, 2013). The proposed mechanism of neuroprotection for each of these studies differ, and include the activation of DNA methyltransferase, DNMT3a, upon miR-29c loss (Pandi et al, 2013) and attenuating blood brain barrier disruption and subsequent vasogenic edema formation through relieving miR-29b repression of AQP4 (Wang et al, 2015).…”

Role of MicroRNA29b in Blood–Brain Barrier Dysfunction during Hyperhomocysteinemia: An Epigenetic Mechanism

“…One of the earlier reports suggests that downregulation of miR29b after acute ischemic stroke contributes to neural cell death and infarct size. 7 However, one report describes that upregulation of miR29b after ischemic brain injury promotes neuronal cell death by inhibiting Bcl2L2. 8 As these studies do not throw light on the role of miR29b in BBB disruption and reports about this microRNA are lacking, the significance of our study lies in drawing a clear picture on how miR29b can affect BBB.…”