Adenovirus-Mediated Delivery of Human Kallistatin Gene Reduces Blood Pressure of Spontaneously Hypertensive Rats

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Abstract
Human kallistatin, or human tissue kallikrein-binding protein (HKBP), is a serine proteinase inhibitor (serpin). Transgenic mice overexpressing rat kallikrein-binding protein are hypotensive. To elucidate therapeutic potentials of kallistatin in hypertension, the human kallistatin gene in an adenoviral vector was directly introduced into spontaneously hypertensive rats (SHR) through portal vein injection. The kallistatin cDNA construct (RSV-cHKBP) under the promoter control of Rous sarcoma virus 3′ long terminal repeat (LTR) was incorporated into adenovirus (Ad.RSV-cHKBP). Recombinant kallistatin in 293 cells transfected with RSV-cHKBP or Ad.RSV-cHKBP was measured by ELISA and by its complex formation with tissue kallikrein. A single intraportal vein injection of Ad.RSV-cHKBP at a dose of 8 × 1010 pfu results in a significant reduction of blood pressure of SHR for 4 weeks. Human kallistatin mRNA was detected in the liver, spleen, kidney, aorta, and lung of rats receiving gene delivery. Immunoreactive human kallistatin in rat serum was detected at the highest level 1 day post injection and at lesser amounts in rat tissues. This study shows that adenovirus harboring Ad.RSV-cHKBP produces functional kallistatin, and adenovirus-mediated transfer of the human kallistatin gene reduces blood pressures of SHR. The results suggest that kallistatin may function as a vasodilator in vivo and provide important information for a potential gene therapy approach to hypertension. Adenovirus-mediated gene delivery of human kallistatin via the portal vein produces significant and sustained reduction of the systolic blood pressure in spontaneously hypertensive rats for 4 weeks. The recombinant kallistatin is mainly produced in rat liver and is secreted into the circulation, which contains high levels of immunoreactive human kallistatin. This result indicates that human kallistatin is a potent new vasodilator.