Furin inhibition prevents hypoxic and TGFβ-mediated blood-brain barrier disruption

Abstract

Hypoxic blood-brain barrier (BBB) dysfunction is a common feature of CNS diseases however mechanisms underlying barrier disturbance are still largely unknown. This study investigated the role of transforming growth factor (TGF), a cytokine known to induce expression of the proprotein convertase Furin, in hypoxia-mediated barrier compromise.We show that exposure of brain endothelial cells (ECs) to hypoxia (1% O2) rapidly stimulates their migration. Additional exogenous TGF (0.4nM) exposure potentiated this effect and increased Furin expression in a TGF type I receptor activin-like kinase 5 (ALK5)-dependent manner (prevented by 10M SB431542). Furin inhibition prevented hypoxia-induced EC migration and blocked TGF-induced potentiation suggesting existence of a feedback loop. TGF and Furin were also critical for hypoxia-induced BBB dysfunction. TGF treatment aggravated hypoxiainduced BBB permeability but ALK5 or Furin blockade reversed injury-induced permeability changes. Thus during insult Furin compromises endothelial integrity by mediating the effects of TGF. Targeting the Furin or ALK5 pathway may offer novel therapeutic strategies for improving BBB stability and CNS function during disease.

Exploration of Oxygen-Induced Retinopathy Model to Discover New Therapeutic Drug Targets in Retinopathies

“…In light of the recent finding that TGF-b together with ab-crystallin is associated with EMT and with subretinal scarring (Ishikawa et al, 2016), simultaneous upregulation of both molecules could provide hints about the potential events that ultimately lead to fibrosis in angiogenic retinal diseases. Furthermore, it was recently demonstrated that myeloid cellderived furin, TGF-b activator, is crucial for the angiogenesis in OIR (Vähätupa et al, 2018b), but furin also aggravates hypoxiainduced blood-brain barrier dysfunction (Baumann et al, 2019). Taking together, the upregulation of proteins involved in mechanotransduction and actomyosin network as well as in the TGF-b signaling in OIR during the angiogenic phase may suggest that these processes could be important for angiogenesis, and thus provide a potential therapeutic target.…”

ERBB3-induced furin promotes the progression and metastasis of ovarian cancer via the IGF1R/STAT3 signaling axis

“…Furin is a ubiquitously expressed proprotein convertase implicated in many physiological and pathological processes ( 26 , 27 ). Studies report that it plays a critical role in the maturation of multiple proteins by cleavage at the specific proprotein recognition sequence RXK/RR and is overexpressed in different types of cancer.…”

The association between plasma furin and cardiovascular events after acute myocardial infarction

“…Epithelial Na+ channel (ENaC), which could be active by furin, associates with increased blood pressure [14,21]. However, transforming growth factor (TGF-β) is also activated by furin but it contributes to lower blood pressure [22,23]. BNP activated by furin associates with low blood pressure through its diuretic and vasodilatory actions.…”