Acta Pharmacologica Sinica 2007 December; 28 (12): 1898-1906; doi: 10.1111/j.1745-7254.2007.00677.x

Aim: The overexpression of the human tissue kallikrein (HK) gene can reduce blood pressure and ameliorate the secondary syndromes associated with hypertension in animal models. The current study was designed to investigate hypotensive effect of intramuscular delivery of HK gene.

Methods: We generated an recombinant adeno-associated virus (rAAV) vector expressing human tissue kallikrein under the control of a cytomegalovirus promoter and administered the rAAV-HK vector to a spontaneously hypertensive rat model at a dose of 1×10¹⁰ virons/rat through intramuscular injection.

Results: A persistent, high-level expression of HK post-gene delivery was confirmed by ELISA. The systolic blood pressure in the rats receiving rAAV-LacZ and saline increased from 171.3 mmHg to 182.3 mmHg 28 weeks' post injection. In contrast, the delivery of the HK gene by AAV vectors attenuated the increase of the systolic blood pressure in the treated group. The systolic blood pressure was only slightly lowered (from a level of 174 mmHg to 170.5 mmHg) post-vector administration. The difference in blood pressure between the treated group and the control groups is statistically significant at 12.6 mmHg. The hypotensive effect of rAAV-HK persisted until the end of the testing period. In addition, a significant amelioration of cardiovascular hypertrophy, renal injury, and collagen depositions in the rAAV-HK-treated animals were also observed.

Conclusion: All the effects are comparable with those of intravenous delivery. Therefore, the intramuscular administration of rAAV-HK may be used in gene therapy for hypertension.

Keywords: recombinant adeno-associated virus vector; human tissue kallikrein; intramuscular administration; hypertension; gene therapy; cardiovascular remodeling; spontaneously hypertensive rat