Volume 15, No 9, Sep 2005
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 15 Issue 9, September 2005: 717-724
ORIGINAL ARTICLES
Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase
Fan ZHANG1,2, Chun Lian CHEN1, Jia Qing QIAN2, Jiang Tao YAN1, Katherine CIANFLONE3, Xiao XIAO4, Dao Wen WANG 1,*
1Department of Internal Medicine and Gene Therapy Center of Tongji Hospital, Tongji Medical College, Huazhong University
of Science and Technology, Wuhan 430030, China
2Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030,
China
3 Mike Rosenbloom Laboratory for Cardiovascular Research, McGill University Health Center, Montreal, Quebec H3A 1A1,
Canada
4 Departments of Molecular Genetics and Biochemistry & Gene Therapy Center, University of Pittsburgh, Pittsburgh, PA
15260, USA
Correspondence: Dao Wen WANG(dwwang@tjh.tjmu.edu.cn)
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 adeno-associated 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 hypertension. The mean systolic pressure increased by 14.2±2.5 mm Hg in rAAV·4A1-treated SD rats and decreased by 13.7±2.2 mm Hg in rAAV·anti4A1-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-4A1-treated SHR, CYP4A mRNA in various tissues was probed, especially in kidneys, but 4A1 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.
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