Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase
Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase
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DOI：
10.1038/sj.cr.7290341
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发表时间：
2005-09
期刊：
影响因子：
44.1
通讯作者：
Fan Zhang;Chun-lian Chen;J. Qian;Jiangtao Yan;K. Cianflone;Xiao Xiao-Xiao;Daowen Wang
中科院分区：
文献类型：
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作者：
Fan Zhang;Chun-lian Chen;J. Qian;Jiangtao Yan;K. Cianflone;Xiao Xiao-Xiao;Daowen Wang
花生四烯酸细胞色素P-450（CYP）羟化酶4A在大鼠肾脏中催化花生四烯酸产生19/20-羟基二十碳四烯酸（20-HETE），其在血压调节中起重要作用。然而，关于20-HETE对血压的确切作用，有争议的结果被报道。本研究利用重组腺相关病毒载体（recombinant adeno-associated viral vector，rAAV）将反义4A 1 cDNA和反义4A 1 cDNA分别转染SD大鼠和自发性高血压大鼠（spontaneoushypertensive rats，SHR），观察其长期调节血压的作用，并探讨其在高血压基因治疗中的应用前景。注射rAAV·4A 1后5周，与对照组相比，注射rAAV·4A 1的SD大鼠平均收缩压升高14.2±2.5 mm Hg，注射rAAV·anti 4A 1的SHR大鼠平均收缩压降低13.7±2.2 mm Hg，这些血压变化一直维持到24周实验结束。在4A 1处理的动物中，CYP 4A在各种组织中过表达，但在mRNA和蛋白质水平上优先在肾脏中过表达。在抗4A 1处理的SHR中，检测到各种组织中的CYP 4A mRNA，尤其是肾脏，但4A 1蛋白表达几乎完全被抑制。这些结果表明，花生四烯酸羟化酶不仅有助于维持正常的血压，但也高血压的发展。rAAV介导的anti 4A给药策略有可能通过阻断肾脏中anti 4A的表达而用作人类高血压的靶向基因治疗。
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.