Chao J, Jin L, Chen L M, Chen V C, Chao L
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425-2211, USA.
Hum Gene Ther. 1996 May 20;7(8):901-11. doi: 10.1089/hum.1996.7.8-901.
There is an inverse correlation between systemic blood pressure and urinary kallikrein levels in humans and hypertensive animal models, suggesting that the tissue kallikrein-kinin system plays an important role in blood pressure regulation. In this study, we explored the potential of human kallikrein gene delivery on blood pressure reduction in spontaneously hypertensive rats (SHR). The human tissue kallikrein gene or cDNA was placed under the control of following promoters: the metallothionein gene metal response-element (MRE-pHK), albumin gene (ALB-pHK), Rous sarcoma virus 3' long terminal repeat (LTR) (RSV-cHK), and cytomegalovirus (CMV-cHK). A single injection of these kallikrein DNAs results in a significant reduction of blood pressure in SHR, which lasts for 5-6 weeks. Systemic delivery of CMV-cHK, RSV-cHK, and MRE-pHK has a greater effect on blood pressure reduction than ALB-pHK, whereas intraportal vein gene delivery of ALB-pHK is more effective than the other kallikrein DNA constructs. The degree of blood pressure reduction depends on the amount of administered DNA and the age of the animals. Reduction of blood pressure was observed in adult, but not young, SHR. The expression of human tissue kallikrein in rats was identified by an ELISA that is specific for human tissue kallikrein. No antibodies to either human tissue kallikrein or its DNA were detected in rat sera after somatic gene delivery. These results show that somatic gene delivery of human tissue kallikrein causes a lowering effect of systolic blood pressure in genetically hypertensive rats and provide valuable information for kallikrein gene therapy in the treatment of hypertension.
在人类和高血压动物模型中，全身血压与尿激肽释放酶水平呈负相关，这表明组织激肽释放酶-激肽系统在血压调节中起重要作用。在本研究中，我们探讨了人激肽释放酶基因递送对自发性高血压大鼠（SHR）血压降低的潜力。人组织激肽释放酶基因或cDNA置于以下启动子的控制下：金属硫蛋白基因金属反应元件（MRE-pHK）、白蛋白基因（ALB-pHK）、劳斯肉瘤病毒3'长末端重复序列（LTR）（RSV-cHK）和巨细胞病毒（CMV-cHK）。单次注射这些激肽释放酶DNA可使SHR血压显著降低，持续5至6周。全身递送CMV-cHK、RSV-cHK和MRE-pHK对血压降低的作用比ALB-pHK更大，而门静脉基因递送ALB-pHK比其他激肽释放酶DNA构建体更有效。血压降低的程度取决于所施用DNA的量和动物的年龄。在成年SHR中观察到血压降低，但在幼年SHR中未观察到。通过对人组织激肽释放酶特异的ELISA鉴定大鼠中人组织激肽释放酶的表达。在体细胞基因递送后，大鼠血清中未检测到针对人组织激肽释放酶或其DNA的抗体。这些结果表明，人组织激肽释放酶的体细胞基因递送可使遗传性高血压大鼠的收缩压降低，并为激肽释放酶基因治疗高血压提供了有价值的信息。
