Long non coding RNAs lncRNAs
Long non-coding RNAs (lncRNAs) are a class of RNA transcripts which are over 200 nucleotides in length and not translated into proteins (Ponting et al., 2009). Recent studies showed that lncRNAs have been identified as crucial regulators of gene expression, chromatin remodeling, and cell cycle (Wahlestedt, 2013). LncRNAs are highly expressed in the Aprotinin australia and implicated in multiple neural diseases, such as autism spectrum disorder and epilepsy (Barry, 2014). Zhang et al. observed significant changes in the expression profiles of many lncRNAs in brain microvascular endothelium after oxygen glucose deprivation (OGD) (Zhang et al., 2016), suggesting a potential role of lncRNAs in mediating endothelial responses to ischemia stroke. Small nucleolar RNA host gene 1 (SNHG1) is a newly discovered lncRNA which is expressed in many types of cancer, including gastric cancer and liver cancer (Hu et al., 2017, Zhang et al., 2016). At 24 h after OGD, SNHG1 expression was increased approximately by 6-fold in BMEC (Zhang et al., 2016). However, the function of SNHG1 in cerebral vasculature after stroke is poorly understood.
MicroRNAs (miRNAs) are endogenous non-coding RNAs which posttranscriptionally inhibit gene expression (Bartel, 2004). MiRNAs have been reported to regulate a variety of pathways including gene expression, cell differentiation, immune response and tumor progression (Alvarez-Garcia and Miska, 2005). Aberrant expression of microRNA was associated with ischemia stroke (Dykstra-Aiello et al., 2016). Serum miR-338 (also miR-338-3p) expression levels were increased in ischemia stroke patients (Peng et al., 2015). Additionally, in hepatocellular carcinoma cells, miR-338 inhibition upregulated MMP9 which plays a critical role in the pathogenesis of post-ischemia BBB disruption (Huang et al., 2011). Therefore, we speculated that miR-338 may participate in the endothelial response to ischemia stroke.
Hypoxia-inducible factor-1 alpha (HIF-1α), a critical regulator of hypoxia, mediates a number of endogenous adaptive mechanisms to adapt cells to low oxygen conditions by regulating over 80 downstream genes (Benita et al., 2009). Expression of HIF-1α is very low in normoxia condition while ischemia stimulation immediately drive a dramatic elevation of HIF-1α to peak the summit at about 3–12 h, and maintain a relative high level during ischemia while decreased rapidly after reperfusion (Bernaudin et al., 2002, Lu et al., 2016, Sun et al., 2016). Upon stroke, HIF-1α regulates some of its downstream genes, including endothelial growth factor (VEGF) which exert neuroprotective effects by inhibiting programmed cell death, enhancing BBB permeability for glucose and activating antioxidants (Singh et al., 2012). However, the role of HIF-1α/VEGF-A in OGD-induced BMEC injury is rarely investigated. More important, factors regulating HIF-1α under OGD conditions remain to be elucidated.
MiR-338 has been shown to downregulate HIF-1α in hepatocarcinoma cells (Xu et al., 2014). Additionally, SNHG1 is upregulated in OGD-treated BMEC and is a sponge of miR-338 in primary esophageal cancer cells (Zhang et al., 2016, Yan et al., 2017). Therefore, in this study, we used mice primary BMEC cells to test the hypothesis that SNHG1 may protect BMEC from OGD-induced injury by downregulating miR-338, thus upregulating HIF-1α. Our data suggested that SNHG1 silence reduced cell viability in OGD-treated BMEC cells by upregulating miR-338, subsequently suppressing HIF-1α/VEGF.
Discussion BMEC injury or apoptosis induced by ischemia stroke plays an important role in the disruption of BBB which is a promising target of stroke management (Liu et al., 2012). A recent study suggested that lncRNAs may play important roles in BMEC cells after ischemia stroke (Zhang et al., 2016). SNHG1, a lncRNA which was initially associated with cancer cell proliferation (You et al., 2014), was upregulated by 6 fold in OGD-treated BMEC (Zhang et al., 2016). In the present study, we demonstrated that SNHG1 regulated HIF-1α/VEGF-A pathway via targeting miR-338, thus protecting BMEC from OGD-induced injury. To our knowledge, the present study provided evidence that SNHG1 played a protective role in BMEC after OGD by regulating cell apoptosis. These findings are consistent with newly revealed report that SNHG1 exerts protective effects in ischemia stroke (Zhang et al., 2018).