Hsp90 inhibition protects brain endothelial cells against LPS‐induced injury

Abstract

Dysfunction of the blood–brain barrier (BBB) endothelium increases infiltration of lymphocytes and innate immune cells in the brain, leading to the development of neurological disorders. Heat shock protein 90 (Hsp90) inhibitors are anti‐inflammatory agents and P53 inducers, which reduce the production of reactive oxygen species (ROS) in a diverse variety of human tissues. In this study, we investigate the effects of those compounds in LPS‐induced brain endothelial inflammation, by utilizing human cerebral microvascular endothelial cells (hCMEC/D3). Our results suggest that Hsp90 inhibitors suppress inflammation by inhibiting the LPS‐induced signal transducer and activator of transcription 3 (STAT3); and P38 activation. Moreover, those compounds reduce the P53 suppressors murine double minute 2 (MDM2) and murine double minute 4 (MDM4). Immunoglobulin heavy chain binding protein/glucose‐regulated protein 78 (BiP/Grp78)—a key element of endothelial barrier integrity‐was also increased by Hsp90 inhibition. Hence, we conclude that application of Hsp90 inhibitors in diseases related to BBB dysfunction may deliver a novel therapeutic possibility in the affected population.

Heat shock protein 90 inhibition in the endothelium

“…The effects of Hsp90 inhibitors are also applied to brain microvascular cells, a component of the blood brain barrier. Specifically, those compounds protect brain cells against LPS (28) and oxidative stress (28,29); in line with similar P53-mediated effects, in vitro (30,31).…”

Heat shock protein 90: biological functions, diseases, and therapeutic targets

“…97 In summary, the utilization of HSP90 inhibitors in conditions associated with BBB dysfunction holds promising potential for novel therapeutic interventions aimed at benefiting affected populations. 98…”