Premium
Overexpression of Heme Oxygenase‐1 Is Neuroprotective in a Model of Permanent Middle Cerebral Artery Occlusion in Transgenic Mice
Author(s) -
Panahian Nariman,
Yoshiura Masako,
Maines Mahin D.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1999.721187.x
Subject(s) - neuroprotection , heme oxygenase , genetically modified mouse , heme , transgene , middle cerebral artery , occlusion , neuroscience , medicine , pharmacology , chemistry , cardiology , biology , ischemia , gene , biochemistry , enzyme
: Heme oxygenase‐1 (HO‐1, HSP32) is an early gene that isresponsive to an array of pathological conditions including, but not limitedto, hypoxia and cerebral ischemia. HO‐1 cleaves the heme molecule and producescarbon monoxide (CO) and biliverdin (an antioxidant) and is essential for ironhomeostasis. The purpose of this study was to investigate, using transgenic(Tg) mice, whether overexpression of HO‐1 in the brain augments or attenuatescellular injury caused by ischemic stroke. Homozygous HO‐1 Tg mice thatoverexpress HO‐1 under the control of the neuron‐specific enolase promoter(characterized previously) were used. Under halothane anesthesia andnormothermic conditions, wildtype nontransgenic (nTg ; n = 22) and HO‐1 Tg (n= 24) mice were subjected to middle cerebral artery occlusion (MCAo). Sixhours after induction of ischemia, Tg and nTg mice developed infarcts thatwere 39 ± 6 and 63 ± 9 mm 3 , respectively ( p < 0.01). No significant difference between the two strains was observed inthe values of brain edema (11.3 ± 4% in Tg vs. 14.6 ± 5% in nTg; p < 0.1). At 24 h after MCAo, Tg mice exhibited significantneuroprotection as determined by the stroke volumes (41 ± 2mm 3 in Tg vs. 74 ± 5 mm 3 in nTg ; p <0.01) and values of ischemic cerebral edema (21 ± 6% in Tg vs. 35± 11% in nTg ; p < 0.01). Data suggest that neuroprotection in Tg mice was, at least in part, related to the following findings : (a) constitutively up‐regulated cyclic GMP and bcl‐2 levels in neurons ; (b) inhibition of nuclear localization of p53 protein ; and (c) antioxidant action of HO‐1, as detected by postischemic neuronal expression of ferritin, and decreases in iron staining and tissue lipid peroxidation. We suggest that pharmacological stimulation of HO‐1 activity may constitute a novel therapeutic approach in the amelioration of ischemic injury during the acute period of stroke.