title: Autoregulation of inducible nitric oxide synthase expression by RNA interference provides neuroprotection in neonatal rats.
abstract: We have shown that autoregulation of gene expression by RNA interference is achievable in cell cultures. To determine whether this novel concept could be used to produce neuroprotection under in vivo condition, postnatal day (PND) 3 rats received intracerebroventricular injection of lentivirus that carried or did not carry code for short hairpin RNA (shRNA) of inducible nitric oxide synthase (iNOS). The expression of this shRNA was controlled by an iNOS promoter (piNOS-shRNA) or cytomegalovirus promoter (pCMV-shRNA). The rats were subjected to brain hypoxia-ischemia at PND7. Ischemic brain tissues had increased iNOS expression. This increase was attenuated by virus carrying piNOS-shRNA. Virus carrying pCMV-shRNA reduced iNOS to a level that was lower than control. Brain tissue loss and functional impairment after the hypoxia-ischemia were attenuated by the virus carrying piNOS-shRNA but not by pCMV-shRNA. Our results provide proof-of-concept evidence that autoregulation of iNOS expression by RNA interference induces neuroprotection in vivo and that appropriate regulation of gene expression is important.
authors.affiliation: 1. Department of Anesthesiology, University of Virginia, Charlottesville, Virginia ; 2. Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 1. Department of Anesthesiology, University of Virginia, Charlottesville, Virginia.
authors.forename: Chenzhuo
authors.initials: C
authors.lastname: Feng
authors.affiliation: 1. Department of Anesthesiology, University of Virginia, Charlottesville, Virginia.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Zhao
authors.affiliation: 1. Department of Anesthesiology, University of Virginia, Charlottesville, Virginia.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Ren
authors.affiliation: 2. Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Shuling
authors.initials: S
authors.lastname: Peng
authors.affiliation: 1. Department of Anesthesiology, University of Virginia, Charlottesville, Virginia.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D002534:Hypoxia, Brain / Q000517:prevention & control*; D020925:Hypoxia-Ischemia, Brain / Q000150:complications*; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D052247:Nitric Oxide Synthase Type II
keywords: autoregulation of gene expression; inducible nitric oxide synthase; neonate; neuroprotection; rats.