Abstract
Hypoxia inducible factor-1α facilitates cellular adaptation to hypoxic conditions. Hence its tight regulation is crucial in hypoxia related diseases such as cerebral ischemia. Changes in hypoxia inducible factor-1α expression upon cerebral ischemia influence the expression of its downstream genes which eventually determines the extent of cellular damage. MicroRNAs are endogenous regulators of gene expression that have rapidly emerged as promising therapeutic targets in several diseases. In this study, we have identified miR-335 as a direct regulator of hypoxia inducible factor-1α and as a potential therapeutic target in cerebral ischemia. MiR-335 and hypoxia inducible factor-1α mRNA showed an inverse expression profile, both in vivo and in vitro ischemic conditions. Given the biphasic nature of hypoxia inducible factor-1α expression during cerebral ischemia, miR-335 mimic was found to reduce infarct volume in the early time (immediately after middle cerebral artery occlusion) of embolic stroke animal models while the miR-335 inhibitor appears to be beneficial at the late time of stroke (24 hrs after middle cerebral artery occlusion). Modulation of hypoxia inducible factor-1α expression by miR-335 also influenced the expression of crucial genes implicated in neurovascular permeability, cell death and maintenance of the blood brain barrier. These concerted effects, resulting in a reduction in infarct volume bring about a beneficial outcome in ischemic stroke.
Highlights
Stroke is one of the leading causes of death and adult disability worldwide. microRNAs have been found to be involved in stroke pathogenesis [1] and to date, numerous miRNAs have been identified to participate in the molecular processes involved in the ischemic cascade [2]
As miR-335 modulation could directly regulate Hif-1a and improve cell viability during oxygen-glucose deprivation (OGD), the attempt was to investigate whether such regulation was reflected in an in vivo setting. miR-335 was differentially expressed upon cerebral ischemia in our eMCAo model and it peaked at 24 hrs which corresponded to the maximum infarct volume (Fi 4A)
To understand the interaction of miR-335 and Hif-1α in in vitro ischemic model, we have demonstrated that modulation of miR-335 expression could affect cell viability in an in vitro ischemic condition and this occurs via regulation of Hif-1a (Fig 3)
Summary
Stroke is one of the leading causes of death and adult disability worldwide. microRNAs (miRNAs) have been found to be involved in stroke pathogenesis [1] and to date, numerous miRNAs have been identified to participate in the molecular processes involved in the ischemic cascade [2]. Stroke is one of the leading causes of death and adult disability worldwide. MicroRNAs (miRNAs) have been found to be involved in stroke pathogenesis [1] and to date, numerous miRNAs have been identified to participate in the molecular processes involved in the ischemic cascade [2]. The interaction of these miRNAs and their specific target mRNAs during. MiRNA-335 Targets Hif-1α cerebral ischemia is poorly understood. Rt-PA (recombinant tissue plasminogen activator) is the only FDA approved drug used to treat ischemic stroke. Its narrow therapeutic window of 4.5 hrs and associated risks such as hemorrhagic transformation have limited its therapeutic potential to only 8% of the ischemic stroke population [3]. There is a pressing need to search for an alternative therapy for ischemic stroke
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