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

Abstract

Although blood-brain barrier (BBB) integrity is maintained by the cross-talk of endothelial cells, junction proteins, and neurogliovascular network, the epigenetic mechanisms behind BBB permeability are largely unknown. We are reporting for the first time miR29b-mediated regulation of BBB, which is a novel mechanism underlying BBB integrity. We hypothesize that miR29b regulates BBB dysfunction by regulating DNMT3b, which consequently regulates the levels of metalloproteinases, that can eat up the membrane and junction proteins leading to leaky vasculature. In addition, 5 0 -azacytidine (5 0 -aza) was used to test its efficacy on BBB permeability. Blood-brain barrier disruption model was created by using homocysteine, and in the models miR29b was identified to be most affected, by using microRNA RT 2 -qPCR array. MiR29b mimics and inhibitors also confirmed that miR29b regulates the levels DNMT3b and MMP9. In hyperhomocysteinemic cystathionine-b-synthase deficient (CBS þ / À ) mice with high brain vessel permeability, miR29b levels were also high as compared with wild-type (WT) mice. Interestingly, 5 0 -aza improved BBB permeability by decreasing the expression of miR29b. In conclusion, our data suggested miR29b-mediated regulation of BBB dysfunction through DNMT3b and MMP9. It also potentiates the use of microRNAs as candidates for future epigenetic therapies in the improvement of BBB integrity.

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

“…MiR-155, miR-181c, and miR-29c negatively affect BBB function by targeting tight junction protein genes directly or affecting related signal pathways. [9][10][11] The miR-34 family members were discovered computationally and later verified experimentally as a part of the p53 tumor suppressor network. Recent work demonstrates that miR-34a modulates the expression of synaptic targets and neuronal morphology and function.…”

Inhibition of MMP-9 attenuates hypertensive cerebrovascular dysfunction in Dahl salt-sensitive rats

“…Brain tissues from different rat groups were collected; homogenized in 0.1 M phosphate buffer (pH 7.4); and the levels of malondialdehyde, glutathione, nitrite, and thiosulfate were quantitated as described earlier [15, 22], with certain modifications. A brief description of the different tests is given below.…”

“…MMPs are induced under oxidative and vascular nitrosative stress and actively participate in the remodeling of cerebral blood vessels [13, 14]. MMPs are expressed in various cell types, including ECs, and are involved in various functions such as; subendothelial matrix (SEM) degradation, extracellular matrix (ECM) and vascular remodeling [15, 16]. We have previously shown the involvement of MMP-9 in cerebrovascular dysfunction [17, 18], by degrading the cerebral vasculature.…”

“…We have previously shown the involvement of MMP-9 in cerebrovascular dysfunction [17, 18], by degrading the cerebral vasculature. Our lab including others clearly showed that MMP-9 attenuation can ameliorate cerebral pathologies [15, 18–20]. Although there is extensive literature on MMP-9 mediated cerebral pathologies, its role in hypertension-induced cerebrovascular pathologies is not explored much.…”

Forebrain Ischemic Stroke and the Phenomenon of Ischemic Tolerance: Is Homocysteine Foe or Friend?

“…Earlier genetic studies suggest that polymorphisms of the genes, which encode the metabolic pathways, such as methylenetetrahydrofolate reductase MTHFR , cystathionine β-synthase C"S , DN" methyltransferase DNMT , and nicotinamide N-methyltransferase NNMT , might play an important role in stroke development during elevated level of Hcy. "dditionally, nutritional supplements, for example, folic acid a cofactor in one-carbon metabolism , can regulate the epigenetic alterations of neuronal cells and may play an important role in the maintenance of neuronal integrity [18,20].…”