Transcription factor early growth response‐1 induction mediates inflammatory gene expression and brain damage following transient focal ischemia

Abstract

Early growth response‐1 (Egr1) is a sequence‐specific transcription factor (TF) which is induced under hypoxic conditions. We presently report that transient middle cerebral artery occlusion (MCAO) leads to increased expression of Egr1 in the brains of adult mice and rats between 2 h and 5 days of reperfusion with a peak increase of 8–12‐fold at 1 day. When subjected to transient MCAO and 3 days of reperfusion, Egr1−/− mice showed significantly smaller infarcts (by 44.9 ± 8.4%, p < 0.05) and improved neurological function than Egr1+/+ littermates. Following transient MCAO, brains of Egr1−/− mice showed less water accumulation and decreased neutrophil infiltration (by 42 ± 8%, p < 0.05) compared to Egr1+/+ mice. The number of activated microglia/macrophages were also significantly lower (OX42+ cells by 53 ± 9%, p < 0.05 and ED1+ cells by 59 ± 11%) in the post‐ischemic cortex of Egr1−/− mice compared to Egr1+/+ mice. In addition, post‐ischemic inflammatory gene expression was less pronounced in the brains of Egr1−/− mice compared to Egr1+/+ mice. Preventing cerebral Egr1 protein induction with small interference RNAs that target Egr1 decreased inflammatory gene expression and led to smaller infarcts (by 40.2 ± 6.9%, p < 0.05) and reduced neurological deficits in rats subjected to transient MCAO. Conversely, transient MCAO following adenoviral‐mediated Egr1 over‐expression exacerbated the infarct volume (by 29 ± 5.3%, p < 0.05) and worsened the neurological deficits in rats. These studies indicate Egr1 as a significant contributor of inflammation and neuronal damage after stroke.

Egr-1 TransactivatesBimGene Expression to Promote Neuronal Apoptosis

“…The induction of Bim has been observed in neuronal apoptosis induced by the Alzheimer's disease-associated amyloid-␤ peptide (Biswas et al, 2007b), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model and cellular model of Parkinson's disease (Liou et al, 2005;Perier et al, 2007), and in focal ischemia models (Okuno et al, 2004;Gao et al, 2005). Intriguingly, amyloid-␤ peptide resulted in enhanced DNA binding activity of Egr-1 (Giri et al, 2003), and the upregulation of Egr-1 has also been found in mouse brain after MPTP treatment (Smith et al, 1997) or transient focal ischemia (Tureyen et al, 2008). Thus, it will be interesting to examine whether Egr-1 transactivates Bim to promote neuronal death in the animal models of many neurological diseases such as Alzheimer's disease, Parkinson's disease, and stroke.…”

“…In the CNS, Egr-1 induction is observed in animal models of neuronal death-related diseases, such as Parkinson's disease (Smith et al, 1997) and ischemia (Tureyen et al, 2008). Although it has been reported that Egr-1 is upregulated (Catania et al, 1999) and plays a crucial role in the activity deprivation-induced apoptosis of CGNs (Levkovitz and Baraban, 2001), its direct targets in neuronal apoptosis are unknown.…”

Induction of Early Growth Response-1 Mediates Microglia Activation In Vitro But is Dispensable In Vivo

“…Egr-1 functions as a key transcription factor of inflammatory gene expression involved in atherosclerosis (Harja et al 2004;Yan et al 2006). Following tissue injury, Egr1 seems to be essential for triggering inflammatory gene induction in different organs including liver , pancreas (Ji et al 2003), lung (Okada et al 2001), and brain (Okada et al 1994;Tureyen et al 2008). Several reports implicate Egr1 in early hematopoietic lineage differentiation (Krishnaraju et al 2001;Nguyen et al 1993) and macrophage maturation (Krishnaraju et al 1995), whereas other studies could not identify major changes in macrophage populations in Egr1 -/-mice (Lee et al 1995;Lee et al 1996).…”

Gene and protein analysis of brain derived neurotrophic factor expression in relation to neurological recovery induced by an enriched environment in a rat stroke model

“…We previously found that animals in an enriched housing group showed a decrease in Early growth response-1 (Erg-1) mRNA [16], which is an inflammatory gene associated with exacerbation of neurological deficits after stroke [18]. To clarify the mechanisms of enriched environment-induced functional recovery, future investigations of neurotrophic factors other than BDNF (i.e., nerve growth factor, neurotrophin-3, and neurotrophin-4) and other inflammatory genes will be needed.…”