LncRNA Blnc1 mediates the permeability and inflammatory response of cerebral hemorrhage by regulating the PPAR-γ/SIRT6/FoxO3 pathway

Abstract

Aims: Intracerebral hemorrhage (ICH) induces serious neuroinflammation and damage of blood-brain barrier. We aim to investigate the role of brown fat enriched lncRNA 1 (Blnc1) in the development of ICH in mice.

Methods: An ICH model was established with autologous blood injection in C57BL/6 mice, and Blnc1 siRNA was injected intracranially. Blnc1 levels were detected and brain injury was evaluated at day 3. Primary brain microvascular endothelial cells (BMVECs) were isolated from new born mice and gain- and loss-of-function experiments were performed to investigate the role of Blnc1. Then, ICH cell model was established by treating BMVECs with oxygen and glucose deprivation (OGD) plus hemin, and Blnc1 siRNA was transfected into the cells. BMVEC functions, including viability, invasion, apoptosis, permeability and secretion of inflammatory cytokines were analyzed.

Key findings: Blnc1 was upregulated in perihematomal edema, hematoma and microvessel in the brain of ICH mice. Blnc1 negatively regulated viability and migration, and facilitated apoptosis, permeability and inflammatory cytokine secretion in BMVECs. Silencing Blnc1 restrained OGD plus hemin-caused reduction of BMVEC viability and migration and the induction of apoptosis, permeability and inflammation response, and suppressed PPAR-γ/SIRT6-mediated FoxO3 activation, which could be reversed by T0070907 (PPAR-γ inhibitor). Downregulation of Blnc1 ameliorated ICH-induced nerve injury, brain edema, blood brain barrier destruction, inflammation response and hematoma. Moreover, Blnc1 levels were positively correlated with PPAR-γ levels, and Blnc1 interference suppressed PPAR-γ/SIRT6-mediated activation of FoxO3 signaling in ICH mice.

Significance: Silencing Blnc1 alleviated nerve injury and inflammatory response caused by ICH through activating PPAR-γ/SIRT6/FoxO3 pathway.

Keywords: Brain microvascular endothelial cells; Brown fat-enriched lncRNA 1; Inflammation; Intracerebral hemorrhage; Peroxisome proliferator activated receptor-γ.