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.
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.
Shin
Hwa Kyoung
HK
Department of Pharmacology and Internal Medicine, College of Medicine, Research Institute of Genetic Engineering, Pusan National University, Seo-Gu, Busan, South Korea.
Lee
Jeong Hyun
JH
Kim
Chi Dae
CD
Kim
Yong Ki
YK
Hong
Jae Yong
JY
Hong
Ki Whan
KW
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
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