miR-98 reduces endothelial dysfunction by protecting blood–brain barrier (BBB) and improves neurological outcomes in mouse ischemia/reperfusion stroke model

Abstract

Most neurological diseases, including stroke, lead to some degree of blood–brain barrier (BBB) dysfunction. A significant portion of BBB injury is caused by inflammation, due to pro-inflammatory factors produced in the brain, and by leukocyte engagement of the brain endothelium. Recently, microRNAs (miRNAs) have appeared as major regulators of inflammation-induced changes to gene expression in the microvascular endothelial cells (BMVEC) that comprise the BBB. However, miRNAs’ role during cerebral ischemia/reperfusion is still underexplored. Endothelial levels of miR-98 were significantly altered following ischemia/reperfusion insults, both in vivo and in vitro, transient middle cerebral artery occlusion (tMCAO), and oxygen–glucose deprivation (OGD), respectively. Overexpression of miR-98 reduced the mouse’s infarct size after tMCAO. Further, miR-98 lessened infiltration of proinflammatory Ly6CHI leukocytes into the brain following stroke and diminished the prevalence of M1 (activated) microglia within the impacted area. miR-98 attenuated BBB permeability, as demonstrated by changes to fluorescently-labeled dextran penetration in vivo and improved transendothelial electrical resistance (TEER) in vitro. Treatment with miR-98 improved significantly the locomotor impairment. Our study provides identification and functional assessment of miRNAs in brain endothelium and lays the groundwork for improving therapeutic approaches for patients suffering from ischemic attacks.

Let-7g* and miR-98 Reduce Stroke-Induced Production of Proinflammatory Cytokines in Mouse Brain

“…Conversely, the let-7 miR family member, miR-98, was shown to bind to and strongly reduce IP-10, which corresponds to the let-7-specific reduction of brain-infiltrating T-cells (Bernstein et al, 2019). These findings are in line with current research which indicates let-7s are critical for mediating endothelial-T cell interactions, and may exert a different effect on the neurovasculature, though some elements are common to both miRs.…”

“…In our previous investigations into the role of let-7 miRs in regulating post-stroke recovery, we determined that miR-98 overexpression reduces the infiltration of monocytes into the ischemic brain, and appears to attenuate the activation of microglia into a proinflammatory state (Bernstein et al, 2019). Conversely, let-7g* was more effective at limiting the infiltration of neutrophils, and other forms of T-cells (Bernstein et al, 2020).…”

“…Restoration of endogenous expression of miR-98 (Bernstein et al, 2019) or let-7g* (Bernstein et al, 2020) can prevent a significant degree of damage following ischemia. However, the mechanisms through which this occurs may be widely different.…”

The transcription factor Foxd3 induces spinal cord ischemia-reperfusion injury by potentiating microRNA-214-dependent inhibition of Kcnk2

“…All of the above plasmids were supplied by Shanghai Gene-Pharma Co., Ltd. (Shanghai, China). The dosages used for mimic NC and miR-214 mimic were 50 nM 20,21 , and 20 nM was used for pcDNA3.1, pcDNA3.1-Kcnk2, sh-NC and sh-Foxd3 22 . After 24 h of transfection, the cells underwent hypoxia (2 h) and reoxygenation (22 h) and were the collected for subsequent experiments.…”

Exosome-Shuttled circSHOC2 from IPASs Regulates Neuronal Autophagy and Ameliorates Ischemic Brain Injury via the miR-7670-3p/SIRT1 Axis

“…Ischemic stroke is a central nervous system disease and one of the main causes of permanent morbidity and disability worldwide. 1 , 2 Therefore, there is a continued need to elucidate novel molecular mechanisms and identify therapeutic targets to control the severity of ischemic stroke. To develop ideal therapeutic methods and expand therapeutic targets, therapeutic approaches that are beneficial to a variety of cell types must be considered.…”