Adenovirus-mediated human tissue kallikrein gene delivery inhibits neointima formation induced by interruption of blood flow in mice.
Tissue kallikrein cleaves kininogen to produce vasoactive kinin peptides. Binding of kinins to bradykinin B(2) 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 1.8 x 10(9) 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 B(2) 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 B(2) 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 B(2) 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.
Emanueli
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Laboratorio di Patologia Vascolare, Istituto Dermapatico dell'Immacolata, Istituto di ricovero e Cura a Carattere Scientifico, Rome, Italy [corrected]. emanueli@yahoo.com
Salis
M B
MB
Chao
J
J
Chao
L
L
Agata
J
J
Lin
K F
KF
Munaò
A
A
Straino
S
S
Minasi
A
A
Capogrossi
M C
MC
Madeddu
P
P
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001158:Arteries / Q000502:physiology*; D017536:Carotid Artery, Common / Q000601:surgery; D000242:Cyclic AMP / Q000652:urine; D006152:Cyclic GMP / Q000652:urine; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006439:Hemodynamics; D018056:Hemorheology; D006801:Humans; D007705:Kinins / Q000652:urine; D008026:Ligation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014018:Tissue Distribution; D020840:Tissue Kallikreins / Q000235:genetics*; D017539:Tunica Intima / Q000502:physiology*
D007705:Kinins; D000242:Cyclic AMP; D020840:Tissue Kallikreins; D006152:Cyclic GMP