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    • Apoptosis signal regulating kinase ASK also referred to as M

    2024-03-13

    Apoptosis signal-regulating kinase 1 (ASK1, also referred to as MAP3K5)(Ichijo et al., 1997) participates in many different stress responses, including apoptosis (Chang et al., 1998, Chen et al., 1999, Ichijo et al., 1997, Kanamoto et al., 2000, Noguchi et al., 2008, Saitoh et al., 1998, Tobiume et al., 2001, Wang et al., 1999, Wendt et al., 1994), cytokine secretion(Matsuzawa et al., 2005) and cell differentiation (Sayama et al., 2001, Takeda et al., 2000). ASK1 is activated in response to various stresses, including oxidative stress, endoplasmic reticulum (ER) stress (Hattori et al., 2009, Matsukawa et al., 2004, Takeda et al., 2003). Several studies have demonstrated that ASK1 overexpression induces apoptosis in various cell types (Chang et al., 1998, Saitoh et al., 1998). Ischemic stroke leads to disruption of the blood–brain barrier (BBB), which subsequently causes vasogenic edema (Unterberg et al., 2004) and cytotoxic edema (Loreto and Reggio, 2010, Nag et al., 2009, Simard et al., 2007), with the latter characterized as swelling of the astrocytes and neuronal dendrites (Risher et al., 2009). Cytotoxic edema occurs shortly after ischemic onset and is the results of translocation of interstitial water into the intracellular compartment (Betz et al., 1989, Young et al., 1987). Vasogenic edema disrupts cerebrovascular endothelial tight junctions, leading to increased permeability to albumin and other plasma proteins (Unterberg et al., 2004), and elevated intracranial pressure (Nag et al., 2009). Finally, vasogenic edema results in water accumulation in damaged IWP-L6 areas (Nag et al., 2009, Yang and Rosenberg, 2011). Reperfusion after occlusion induces overpressure accompanied by shear stress (Hirt et al., 2009, Ribeiro et al., 2006) and leads to further entry of water through endothelial cells, resulting in brain swelling (Hirt et al., 2009, Ribeiro Mde et al., 2006) and further increases BBB permeability (Hirt et al., 2009, Strbian et al., 2008). According to previous studies, edema and cerebral infarction are especially exacerbated during ischemia/reperfusion (I/R) (Bleilevens et al., 2013). Hypoxic (low level of oxygen) and ischemic (low levels of oxygen and glucose) states caused by stroke also activate ASK1 (Bitto et al., 2010, Harding et al., 2010, Kwon et al., 2005). One study demonstrated that the increased ASK1 expression triggers apoptotic cell death after IR, whereas ASK1-small interference RNA (siRNA) attenuates ASK1 upregulation and reduces infarction in ischemic brain (Kim et al., 2011). Another study reported that anti-ASK1 short hairpin RNA (shRNA) suppresses ASK1 in the oxidative stress state induced by cerebral I/R (An et al., 2013). Several studies suggested that an ischemic state leads to dissociation of thioredoxin (Trx) from ASK1 by reactive oxygen species (ROS) generation and induces the activation of ASK1-mediated apoptosis pathways (e.g., the p38 pathway) (Ke and Costa, 2006). Activated p38 triggers the phosphorylation of hypoxia-inducible factor-1-a (HIF1-α), which modulates the expression of various target genes encoding proteins under hypoxic conditions (Ke and Costa, 2006, Kwon et al., 2005). Vascular endothelial growth factor (VEGF), an important HIF1-α target gene and vascular permeabilizing factor (Fischer et al., 1999, Minchenko et al., 1994) is induced by hypoxia and decreases the expression of BBB tight junction proteins (Keck et al., 1989), such as ZO-1 (Fischer et al., 2002, Yeh et al., 2007) and occludin(Fischer et al., 2002, Luissint et al., 2012). Furthermore, VEGF induces BBB disruption and vasogenic edema (Kimura et al., 2005, Roberts and Palade, 1995, Sood et al., 2008, van Bruggen et al., 1999, Wang and Tsirka, 2005) under ischemic stroke. Considering research into the role of ASK1 in ischemia-induced angiogenesis in vivo, ASK1 is involved in VEGF expression in ischemic tissue and promotes early angiogenesis by stimulating VEGF expression (Izumi et al., 2005). Aquaporin (AQP)-1, a family of water channels, is known as a water-selective transporting protein in cell membranes as CHIP28 (CHannel-like Integral membrane Protein of 28kDa) (Agre et al., 1993, Smith and Agre, 1991). In hypoxic conditions, AQP-1 expression is upregulated in human endothelial cells (Kaneko et al., 2008). AQP-1 activity is stimulated by hypertonicity and is regulated by ERK, p38, and JNK activation (Umenishi and Schrier, 2003) and is associated with stress-induced endothelial cell migration (Saadoun et al., 2005). In present study, we investigated whether ASK1 affects vascular permeability and edema formation after ischemic brain injury. We show that ASK1 inhibition is linked to the prevention of edema formation under hypoxic injury. Thus, our results suggest that ASK1 regulation might alleviate stroke-induced pathological alterations by protecting the disruption of BBB following cerebral ischemic injury.