ARTICLE

Cell Research, 15(9):717-724, September 2005

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

Fan ZHANG^1,2, 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

Received, Apr 4, 2005 Revised, Sep 8, 2005 Accepted, Sep 15, 2005

Correspondence: Dao Wen WANG Tel: +86-27-8366-2827; Fax: +86-27-8366-2842; E-mail:dwwang@tjh.tjmu.edu.cn

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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.

Keywords: Arachidonic acid, cytochrome P450 4A1, hypertension, recombinant adeno-associated virus, 20-Hydroxyeicosatetraenoic acids, spontaneously hypertensive rats.