Activation of MAP kinase (ERK-1/ERK-2), tyrosine kinase and VEGF in the human brain following acute ischaemic stroke

Abstract

We examined expression of vascular endothelial growth factor (VEGF), phosphorylation of mitogen activated protein kinase (MAP) kinase (ERK1 and ERK2) and tyrosine phosphorylation in 19 patients (aged 58-90 years; mean 75) who died 1-44 days after acute ischaemic stroke. In the grey matter penumbra, 13 of 19 patients showed an increase in MAP kinase tyrosine phosphorylation (ERK1; 2.0- to 8-fold, ERK2; 2.2- to 11-fold) compared with normal contralateral tissue. In almost all cases, ERK-2 phosphorylation was higher than ERK1. Of these 13 patients, 11 also showed a general increase in tyrosine kinase phosphorylation, and eight expressed increased levels of VEGF protein (2.5- to 5-fold). In tissue examined directly from the infarct core, activation of the above proteins was not observed in the, majority of patients. In the white matter, seven of 19 patients (penumbra), and nine of 19 patients (stroke) had an increase in MAP kinase tyrosine phosphorylation (ERK1; 2.0- to 4.6-fold and ERK-2; 2.3- to 5.4-fold respectively) compared with normal contralateral tissue. There was no relationship between activation of MAP kinase and expression of VEGF. Examination of phosphorylated MAP kinase by immunohistochemistry revealed an increase in immunoreactivity in neurones, astroglial cells, reactive microglia and endothelial cells in areas surrounding infarcts, especially in areas with the highest density of microvessels. In conclusion, chronic activation of tyrosine phosphorylated events, in particular redistribution and phosphorylation of MAP kinase (ERK1/ERK2) occurs consistently in the grey matter penumbra of brain tissue following ischaemic stroke, and may be associated with increase in expression of VEGF. These signal transduction events could be important determinants of the extent of neuronal survival and/or angiogenic activity in the recovering brain tissue.

Ionizing radiation modulates vascular endothelial growth factor (VEGF) expression through multiple mitogen activated protein kinase dependent pathways

“…The proliferation of many carcinoma cells in vitro and in vivo is in part regulated by the synthesis and autocrine actions of ligands such as transforming growth factor a (TGFa) Levenson et al, 1998) and vascular endothelial growth factor (VEGF) (Slevin et al, 2000;Hossain et al, 2000;Mazure et al, 1997;Zundel et al, 2000). Irradiation of tumor cells can both increase expression of TGFa and activate the EGFR, and this has been proposed to increase the proliferative rate of surviving cells (Levenson et al, 1998;Baselga et al, 1996;SchmidtUllrich et al, 1992;Putz et al, 1999).…”

“…MAPK signaling has also been linked to increased expression of growth factors such as VEGF (Pages et al, 2000;Rak et al, 2000;Li et al, 2000). Growth factors such as VEGF and TGFa, in addition to a growth promoting role in vitro, may also play an important role in the development of tumors in vivo due to their abilities in the promotion of angiogenesis (Slevin et al, 2000;Hossain et al, 2000;Mazure et al, 1997;Zundel et al, 2000;Pages et al, 2000;Rak et al, 2000;Li et al, 2000;Minet et al, 1999). Collectively, these ®ndings argue that radiation may have a self-limiting e ect on its toxicity via increased activity of EGFR and downstream signaling modules such as the MAPK pathway.…”

Role of Protein Phosphatases in Estrogen-Mediated Neuroprotection

“…Indeed, pharmacological inhibition of ERK1/2 signaling is neuroprotective in a number of cell model systems (Murray et al, 1998;Barone et al, 2001), including the HT-22 cell oxidative stress model used in our studies (Satoh et al, 2000;Stanciu et al, 2000). Similarly, in models of stroke, brain trauma, and neurodegenerative diseases, there are detrimental effects of persistent activation of ERK1/2 during oxidative neuronal injury as well as excitotoxic injury (Alessandrini et al, 1999;Slevin et al, 2000;Stanciu et al, 2000;Zhu et al, 2002a,b;Ferrer et al, 2003;Harper and Wilkie, 2003;Wang et al, 2003Wang et al, , 2004.…”

“…Persistent activation of protein kinase C (PKC) associated with ethanol-induced neurotoxicity has also been shown (Jung et al, 2005). Also, in models of stroke, brain trauma, and neurodegenerative diseases, the detrimental effects of persistent activation of ERK1/2 during oxidative as well as excitotoxic neuronal injury have been documented (Slevin et al, 2000;Stanciu et al, 2000;Zhu et al, 2002a,b;Ferrer et al, 2003;Harper and Wilkie, 2003). Estrogens have been shown to block the persistent activation of both ERK and PKC (Watters et al, 1997;Singh et al, 1999Singh et al, , 2000Bi et al, 2000;Kuroki et al, 2000;Jung et al, 2005) The role of PPs in estrogen-mediated neuroprotection against excitotoxicity and oxidative stress-induced cell death was investigated.…”

Human umbilical cord blood mesenchymal stem cell transplantation suppresses inflammatory responses and neuronal apoptosis during early stage of focal cerebral ischemia in rabbits

“…The MAPK family includes the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. They are activated in response to ischemiareperfusion-induced brain injury, and it is believed that the [27][28][29] . It should be noted that JNK and p38 are activated by proinflammatory cytokines and promote apoptosis [30] .…”