Abstract
Purpose: :
Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase (MAPK) kinase kinase that plays an important role in oxidative stress-induced apoptosis. In this study, we examined whether ASK1 is involved in the neural cell death during retinal development and ischemic injury.
Methods: :
ASK1 expression was examined at embryonic day 15, postnatal day 0 (P0), P7, and P90 by in situ hybridization. Effects of ASK1 during retinal development and ischemic injury were analysed using ASK1 knockout (KO) mice. Localization and expression levels of p38 MAPK and caspase-3 were examined by immunohistochemistry and immunobot analysis. Effect of H2O2 on cultured retinal ganglion cell (RGC) death was examined by lactate dehydrogenase assay.
Results: :
ASK1 is expressed in retinal neurons including RGCs, but retinal structure and extent of cell death during development were normal in ASK1 KO mice. On the other hand, the strain was less susceptible to ischemic injury, and the number of surviving retinal neurons was significantly increased compared with that in wild-type mice. Interestingly, ischemia-induced phosphorylation of p38 MAPK, which mediates RGC apoptosis, was almost completely suppressed in ASK1 KO mice. In such retinas, the number of cleaved caspase-3- and TUNEL-positive neurons were apparently decreased compared with those in wild-type mice. In addition, cultured RGCs from ASK1 KO mice were resistant to H2O2-induced apoptosis. We also crossed ASK1 KO mice with glutamate transporter KO mice, which show typical glaucomatous damage of the optic nerve. Loss of ASK1 partially recovered visual function of glutamate transporter KO mice.
Conclusions: :
Our findings suggest that ASK1 is involved in the neural cell apoptosis in various pathological conditions. Thus, inhibition of ASK1-p38 pathway could be potentially useful for the treatment of neurodegenerative diseases including glaucoma.
Keywords: apoptosis/cell death • retina: proximal (bipolar, amacrine, and ganglion cells) • pathology: experimental