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MiR-34a regulates blood-brain barrier permeability and mitochondrial function by targeting cytochrome c.

ABSTRACT: The blood-brain barrier is composed of cerebrovascular endothelial cells and tight junctions, and maintaining its integrity is crucial for the homeostasis of the neuronal environment. Recently, we discovered that mitochondria play a critical role in maintaining blood-brain barrier integrity. We report for the first time a novel mechanism underlying blood-brain barrier integrity: miR-34a mediated regulation of blood-brain barrier through a mitochondrial mechanism. Bioinformatics analysis suggests miR-34a targets several mitochondria-associated gene candidates. We demonstrated that miR-34a triggers the breakdown of blood-brain barrier in cerebrovascular endothelial cell monolayer in vitro, paralleled by reduction of mitochondrial oxidative phosphorylation and adenosine triphosphate production, and decreased cytochrome c levels.

SUBMITTER: Bukeirat M

PROVIDER: S-EPMC4759667 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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MiR-34a regulates blood-brain barrier permeability and mitochondrial function by targeting cytochrome c.

Bukeirat Mimi M Sarkar Saumyendra N SN Hu Heng H Quintana Dominic D DD Simpkins James W JW Ren Xuefang X

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20150930 2

The blood-brain barrier is composed of cerebrovascular endothelial cells and tight junctions, and maintaining its integrity is crucial for the homeostasis of the neuronal environment. Recently, we discovered that mitochondria play a critical role in maintaining blood-brain barrier integrity. We report for the first time a novel mechanism underlying blood-brain barrier integrity: miR-34a mediated regulation of blood-brain barrier through a mitochondrial mechanism. Bioinformatics analysis suggests ...[more]

PMID: 26661155

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Project description:BACKGROUND:Acute neurological insults caused by infection, systemic inflammation, ischemia, or traumatic injury are often associated with breakdown of the blood-brain barrier (BBB) followed by infiltration of peripheral immune cells, cytotoxic proteins, and water. BBB breakdown and extravasation of these peripheral components into the brain parenchyma result in inflammation, oxidative stress, edema, excitotoxicity, and neurodegeneration. These downstream consequences of BBB dysfunction can drive pathophysiological processes and play a substantial role in the morbidity and mortality of acute and chronic neurological insults, and contribute to long-term sequelae. Preserving or rescuing BBB integrity and homeostasis therefore represents a translational research area of high therapeutic potential. METHODS:Induction of general and localized BBB disruption in mice was carried out using systemic administration of LPS and focal photothrombotic ischemic insult, respectively, in the presence and absence of the monoacylglycerol lipase (MAGL) inhibitor, CPD-4645. The effects of CPD-4645 treatment were assessed by gene expression analysis performed on neurovascular-enriched brain fractions, cytokine and inflammatory mediator measurement, and functional assessment of BBB permeability. The mechanism of action of CPD-4645 was studied pharmacologically using inverse agonists/antagonists of the cannabinoid receptors CB1 and CB2. RESULTS:Here, we demonstrate that the neurovasculature exhibits a unique transcriptional signature following inflammatory insults, and pharmacological inhibition of MAGL using a newly characterized inhibitor rescues the transcriptional profile of brain vasculature and restores its functional homeostasis. This pronounced effect of MAGL inhibition on blood-brain barrier permeability is evident following both systemic inflammatory and localized ischemic insults. Mechanistically, the protective effects of the MAGL inhibitor are partially mediated by cannabinoid receptor signaling in the ischemic brain insult. CONCLUSIONS:Our results support considering MAGL inhibitors as potential therapeutics for BBB dysfunction and cerebral edema associated with inflammatory brain insults.

Dataset Information

MiR-34a regulates blood-brain barrier permeability and mitochondrial function by targeting cytochrome c.

Publications

MiR-34a regulates blood-brain barrier permeability and mitochondrial function by targeting cytochrome c.

Similar Datasets

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