Kallistatin in blood pressure regulation transgenic and somatic gene delivery studies

Kallistatin, first discovered as a human kallikrein-binding protein in the circulation, shares high homology with other plasma serine proteinase inhibitors (serpins). It forms a covalently linked complex with tissue kallikrein and inhibits kallikrein's activity. Substantial evidence has accumulated in recent years indicating that kallistatin may play a role in blood pressure regulation independent of its interaction with tissue kallikrein. Intravenous injection of kallistatin into rats and mice results in a rapid and transient reduction of blood pressure in a dose-dependent manner. Functional analysis in transgenic mice over-expressing rat kallikrein-binding protein, an analogue of human kallistatin, revealed that these mice have significantly lower blood pressure compared with control littermates. Adenovirus-mediated delivery of the human kallistatin gene can cause significant blood pressure reductions for 4 weeks in spontaneously hypertensive rats. Finally, kallistatin can induce vasorelaxation in isolated rat aortic rings and reduce renal perfusion pressure in the isolated, perfused kidney. Together, these findings suggest a direct role for kallistatin in regulating blood pressure and raise the possibility for the development of new pharmacological treatments for hypertension. (Trends Cardiovasc Med 1997;7:307-311). © 1997, Elsevier Science Inc.