Long-term modifications of blood pressure in normotensive and spontane-ously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase  

作　　者：Fan ZHANG Chun Lian CHEN Jia Qing QIAN Jiang Tao YAN Katherine CIANFLONE Xiao XIAO Dao Wen WANG 

机构地区：[1]Department of Internal Medicine and Gene Therapy Center of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China [2]Department of Pharmacology, Tongji Medical College China Huazhong University of Science and Technology, Wuhan 430030 [3]Mike Rosenbloom Laboratoo, for Cardiovascular Research, McGill University Health Center, Montreal, Quebec H3A 1A1, Canada [4]DepartmentsofMolecular Genetics and Biochemistry ＆ GeneTherapy Center, University of Pittsburgh, Pittsburgh, PA 15260. USA

出　　处：《Cell Research》2005年第9期717-724,共8页细胞研究（英文版）

基　　金：This project Was supported by the National Natural Science Foundation of China(NSFC,No.39870307);National Basic Research Program of China(973 Program,No.G2000056901);KC was the recipient of an Fonds de la recherche en sante du Quebec(FRSQ,Quebec-Canada)-NSFC(China exchange grant).

摘　　要：Arachidonic acid cytochrome P-450 （CYP） hydroxylase 4A isoforms, including 4A1, 4A2, 4A3 and 4A8 in the rat kidney, catalyze arachidonic acid to produce 19/20-Hydroxyeicosatetraenoic acids （20-HETE）, a biologically active metabolite, which plays an important role in the regulation of blood pressure. However, controversial results have been reported regarding the exact role of 20-HETE on blood pressure. In the present study, we used recombinant adenoassociated viral vector （rAAV） to deliver CYP 4A1 cDNA and antisense 4A1 cDNA into Sprague-Dawley （SD） rats and spontaneously hypertensive rats （SHR）, respectively, to investigate the effects of long-term modifications of blood pressure and the potential for gene therapy of hyperténsion. The mean systolic pressure increased by 14.2±2.5 mm Hg in rAAV.4A 1-treated SD rats and decreased by 13.7±2.2 mm Hg in rAAV.anti4A l-treated SHR rats 5 weeks after the injection compared with controls and these changes in blood pressure were maintained until the experiments ended at 24 weeks. In 4A1 treated animals CYP4A was overexpressed in various tissues, but preferentially in the kidney at both mRNA and protein levels. In anti-4Al-treated SHR, CYP4A mRNA in various tissues was probed, especially in kidneys, but 4A l protein expression was almost completely inhibited. These results suggest that arachidonic acid CYP hydroxylases contribute not only to the maintenance of normal blood pressure but also to the development of hypertension. rAAV-mediated anti4A administration strategy has the potential to be used as targeted gene therapy in human hypertension by blocking expression of CYP 4A in kidneys.

关 键 词：Arachidonic acid cytochrome P450 4A1 hypertension recombinant adeno-associated virus 20-Hydroxyeicosatetraenoic acids spontaneously hypertensive rats 

分 类 号：R544.1[医药卫生—心血管疾病]