Jin L, Zhang J J, Chao L, Chao J
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425-2211, USA.
Hum Gene Ther. 1997 Oct 10;8(15):1753-61. doi: 10.1089/hum.1997.8.15-1753.
Tissue kallikrein has been shown to play a role in blood pressure regulation, and abnormalities in the kallikreinkinin system are considered to be a factor in the pathogenesis of hypertension. To elucidate the potential therapeutic effects of kallikrein gene delivery in hypertension, an adenoviral vector containing the human tissue kallikrein gene under the control of a cytomegalovirus promoter, Ad.CMV-cHK, was intravenously injected into spontaneously hypertensive rats (SHR). A single injection of Ad.CMV-cHK into SHR caused a sustained delay in the increase in blood pressure from day 2 to day 41 post injection, as compared to control rats receiving Ad.CMV-LacZ adenovirus. Adenovirus-mediated kallikrein gene delivery had no effect on the blood pressure of normotensive Wistar-Kyoto rats. Human tissue kallikrein mRNA was detected in the liver, kidney, spleen, adrenal gland, and aorta. Immunoreactive human tissue kallikrein can be detected in sera and urine of rats receiving kallikrein gene delivery. Human tissue kallikrein in rat serum was at the highest level 5 days post injection, and the level declined gradually. Urinary kinin and cGMP levels were significantly increased in rats receiving kallikrein gene delivery compared to Ad.CMV-LacZ control rats. These results show that adenovirus-mediated delivery of human tissue kallikrein results in high-efficiency expression and blood pressure reduction in SHR. Application of adenovirus-mediated systemic expression of the tissue kallikrein gene may provide a unique way of delivering the gene product into the vasculature and could have important therapeutic implications in treating hypertension.
组织激肽释放酶已被证明在血压调节中发挥作用，激肽释放酶-激肽系统的异常被认为是高血压发病机制中的一个因素。为了阐明激肽释放酶基因递送对高血压的潜在治疗作用，将一种在巨细胞病毒启动子控制下含有人类组织激肽释放酶基因的腺病毒载体Ad.CMV-cHK静脉注射到自发性高血压大鼠（SHR）体内。与接受Ad.CMV-LacZ腺病毒的对照大鼠相比，向SHR单次注射Ad.CMV-cHK可使注射后第2天至第41天血压升高持续延迟。腺病毒介导的激肽释放酶基因递送对正常血压的Wistar-Kyoto大鼠的血压没有影响。在肝脏、肾脏、脾脏、肾上腺和主动脉中检测到人类组织激肽释放酶mRNA。在接受激肽释放酶基因递送的大鼠的血清和尿液中可检测到免疫反应性人类组织激肽释放酶。大鼠血清中的人类组织激肽释放酶在注射后5天达到最高水平，随后水平逐渐下降。与Ad.CMV-LacZ对照大鼠相比，接受激肽释放酶基因递送的大鼠尿激肽和cGMP水平显著升高。这些结果表明，腺病毒介导的人类组织激肽释放酶递送可导致SHR高效表达并降低血压。应用腺病毒介导的组织激肽释放酶基因全身表达可能提供一种将基因产物递送至脉管系统的独特方式，并且在治疗高血压方面可能具有重要的治疗意义。
