title: Prevention of impairment of cerebral blood flow autoregulation during acute stage of subarachnoid hemorrhage by gene transfer of Cu/Zn SOD-1 to cerebral vessels.
abstract: The present study determined whether gene transfer of human copper/zinc superoxide dismutase-1 (Cu/Zn SOD-1) prevented the autoregulatory impairment of CBF induced by subarachnoid hemorrhage (SAH). After application of recombinant adenovirus (100 microL of 1 x 10(10) pfu/mL, intracisternally) encoding human Cu/Zn SOD-1 3 days before experiments, Cu/Zn SOD-1 activity significantly increased in association with increase in Cu/Zn SOD-1 mRNA and protein expression in the cerebral vasculature of both sham-operated and SAH rats as determined by reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry, and SAH-induced increase in superoxide anion was markedly reduced in accordance with increased nitric oxide production. In line with these findings, rats that received human Cu/Zn SOD-1 therapy showed the prominent restoration of blunted vasodilation of the pial artery in response to calcitonin gene-related peptide and levcromakalim, and the recovery of impaired autoregulatory vasodilation in response to acute hypotension, thereby leading to significant restoration of CBF autoregulation. These results provide a rational basis for application of Cu/Zn SOD-1 gene therapy for protection of the impairment of autoregulatory CBF during the acute stage of SAH.
authors.affiliation: Department of Pharmacology and Internal Medicine, College of Medicine, Research Institute of Genetic Engineering, Pusan National University, Seo-Gu, Busan, South Korea.
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
authors.forename: Yong Ki
authors.initials: YK
authors.lastname: Kim
authors.forename: Jae Yong
authors.initials: JY
authors.lastname: Hong
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Hong
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001158:Arteries / Q000503:physiopathology; D001808:Blood Vessels / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010841:Pia Mater / Q000098:blood supply; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000503:physiopathology*; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism; D019076:Transgenes; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014666:Vasomotor System / Q000503:physiopathology
chemical_list: D009566:Nitrates; D009573:Nitrites; C000606290:SOD1 protein, human; D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019255:NADPH Oxidases