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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1459.)
© 2000 American Heart Association, Inc.

Vascular Biology

Adenovirus-Mediated Human Tissue Kallikrein Gene Delivery Inhibits Neointima Formation Induced by Interruption of Blood Flow in Mice

Costanza Emanueli; Maria Bonaria Salis; Julie Chao; Lee Chao; Jun Agata; Kuei-Fu Lin; Antonella Munaò; Stefania Straino; Alessandra Minasi; Maurizio C. Capogrossi; Paolo Madeddu

From the Gene Therapy Section of the National Laboratory of the National Institute of Biostructures and Biosystems (C.E., M.B.S., A. Munaò, P.M.), Osilo, Italy; Laboratorio di Patologia Vascolare (C.E., S.S., A. Minasi, M.C.C.), Istituto Dermopatico dell’ Immacolata (IDI-IRCCS), Roma, Italy; Institute of Internal Medicine (P.M.), School of Medicine, University of Sassari, Sassari, Italy; and the Department of Biochemistry and Molecular Biology (J.C., L.C., J.A., K.-F.L.), Medical University of South Carolina, Charleston.

Correspondence to Costanza Emanueli, PhD, Gene Therapy Section, National Laboratory of the National Institute of Biostructures and Biosystems, via Brigata Sassari, 13, 07033 Osilo, Sassari, Italy. E-mail emanueli{at}yahoo.com

Abstract—Tissue kallikrein cleaves kininogen to produce vasoactive kinin peptides. Binding of kinins to bradykinin B₂ receptors on vascular endothelial cells stimulates the release of nitric oxide and prostacyclin, thus activating the cGMP and cAMP pathways. In this study, we evaluated the effects of adenovirus-mediated human tissue kallikrein gene (Ad.CMV-cHK) delivery in a mouse model of arterial remodeling induced by permanent alteration in shear stress conditions. Mice underwent ligature of the left common carotid artery and were injected intravenously with saline or 1.8x10⁹ plaque-forming units of Ad.CMV-cHK or control virus (Ad.CMV-LacZ). Fourteen days after surgery, morphometric analysis revealed that Ad.CMV-cHK reduced neointima formation by 52% (P<0.05) compared with Ad.CMV-LacZ. Expression of human tissue kallikrein (HK) mRNA was detected in mouse carotid artery, aorta, kidney, heart, and liver, and recombinant HK was present in the urine and plasma of mice receiving HK gene. Kallikrein gene transfer resulted in increases in urinary kinin, cGMP, and cAMP levels. The protective action of Ad.CMV-cHK on neointima formation was significantly reduced (P<0.05) in mice with knockout of the kinin B₂ receptor gene compared with wild-type control mice (J129Sv mice). In contrast, the effect of Ad.CMV-cHK was amplified (P<0.05) in transgenic mice overexpressing human B₂ receptor compared with wild-type control mice (c57/Bl6 mice). Thus, the inhibitory effect of recombinant kallikrein on structural alterations caused by the interruption of blood flow appears to be mediated by the B₂ receptor. These results provide new insight into the role of the tissue kallikrein-kinin system in vascular remodeling and suggest the application of HK gene therapy to treat restenosis and atherosclerosis.

Key Words: human tissue kallikrein • gene delivery • neointima formation • bradykinin B₂ receptors • mice, transgenic and knockout

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