Molecular chaperones in the brain endothelial barrier: neurotoxicity or neuroprotection?

Abstract

Brain microvascular endothelial cells (BMECs) interact with astrocytes and pericytes to form the blood–brain barrier (BBB). Their compromised function alters the BBB integrity, which is associated with early events in the pathogenesis of cancer, neurodegenerative diseases, and epilepsy. Interestingly, these conditions also induce the expression of heat shock proteins (HSPs). Here we review the contribution of major HSP families to BMEC and BBB function. Although investigators mainly report protective effects of HSPs in brain, contrasted results were obtained in BMEC, which depend both on the HSP and on its location, intra‐ or extracellular. The therapeutic potential of HSPs must be scrupulously analyzed before targeting them in patients to reduce the progression of brain lesions and improve neurologic outcomes in the long term.—Thuringer, D., Garrido, C. Molecular chaperones in the brain endothelial barrier: neurotoxicity or neuroprotection? FASEB J. 33, 11629–11639 (2019). http://www.fasebj.org

Dicarbonyl Stress and S-Glutathionylation in Cerebrovascular Diseases: A Focus on Cerebral Cavernous Malformations

“…In particular, redox proteomic analysis by nLC-ESI-LIT-MS/MS identified distinct proteins that were differentially S-glutathionylated as a function of KRIT1 expression, including important cytoskeletal proteins, such as actin; tubulin beta-4B chain; tropomyosin; and vimentin; the glycolytic enzymes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and alpha-enolase (ENO1), creatine kinase B-type (CKB); and members of the chaperonin family, such as heat shock protein 60 (HSP60) and calreticulin (CALR). Notably, all the identified S-glutathionylated proteins were known to be redox-sensitive and implicated in fundamental biological processes linked to cellular adaptive responses to OS, including the unfolded protein response (UPR), the interplay between oxidant species and energy metabolism, and the cytoskeleton organization and dynamics, as well as in the maintenance of BBB integrity and functionality [163][164][165]. In particular, given that a coordinated dynamics of actin filaments and microtubules is crucial for the regulation of endothelial barrier stability and vascular permeability [166], it is significant that such dynamics are redox-sensitive and may be modulated by S-glutathionylation of major structural and regulatory proteins [15,167].…”

The Role of Exosomal miRNAs in Glioma: Biological Function and Clinical Application

“…For example, the level of circulating exosomal miR-148a in serum of patients with GBM significantly increased and enhanced the proliferation of glioma cell proliferation and facilitated the metastasis by activating the STAT3 signal pathway to inhibit expression of target gene CADM1 (44). Similarly, Thuringer (32) and other researchers (33) found that glioblastoma-derived exosomal miR-5096 continuously stimulated tumor cells to secrete more exosomes containing miR-5096 and increased the number of motor filamentous pseudopodia. In addition, the study also proved the association between the K + channel and GBM.…”

“…Compared to healthy individuals, the expression level of plasma exosomal miR-21 was significantly increased in patients with malignant gliomas (31). Thuringer (32) and other studies (33) indicated that exosomal miR-5096 obtained from patients with GBM promoted the growth of filopodium and the invasion of glioma cells by regulating inward rectifier K + channel Kir4.1. At the The biogenesis of exosome begins at endosome formation through endocytosis at the plasma membrane, and then, early endosomes maturate to multivesicular bodies (MVB).…”

Heat Shock Proteins and PD-1/PD-L1 as Potential Therapeutic Targets in Myeloproliferative Neoplasms

“…It has been reported that HSPs can be secreted through extracellular vesicles (EVs) and that high expression of HSPs in EVs is a negative prognostic factor in metastatic solid cancers [ 137 , 138 ]. Surprisingly, when compared to its intracellular form, extracellular HSP70 has been shown to have a contrasting effect on neuroprotection in certain neurologic disorders [ 139 ]. Finally, extracellular HSPs could also be of great interest for the diagnosis of diseases.…”