Role of heme oxygenase-1 in the regulation of manganese superoxide dismutase gene expression in oxidatively-challenged astroglia

Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme that reduce s superoxide anion to hydrogen peroxide in cell mitochondria. MnSOD is over expressed in normal aging brain and in various central nervous system disor ders; however, the mechanisms mediating the upregulation of MnSOD under the se conditions remain poorly understood. We previously reported that cysteam ine (CSH) and other pro-oxidants rapidly induce the heme oxygenase-1 (HO-1) gene in cultured rat astroglia followed by late upregulation of MnSOD in t hese cells. In the present study, we demonstrate that antecedent upregulati on of HO-1 is necessary and sufficient for subsequent induction of the MnSO D gene in neonatal rat astroglia challenged with CSH or dopamine, and in as troglial cultures transiently transfected with full-length human HO-1 cDNA. Treatment with potent antioxidants attenuates MnSOD expression in HO-1-tra nsfected astroglia, strongly suggesting that intracellular oxidative stress signals MnSOD gene induction in these cells. Activation of this HO-1-MnSOD axis may play an important role in the pathogenesis of Alzheimer disease, Parkinson disease and other free radical-related neurodegenerative disorder s. In these conditions, compensatory upregulation of MnSOD may protect mito chondria from oxidative damage accruing from heme-derived free iron and car bon monoxide liberated by the activity of HO-1. (C) 2000 Wiley-Liss, Inc.