Adenovirus-mediated kallikrein gene transfer inhibits neointima formation via increased production of nitric oxide in rat artery.
Tissue kallikrein cleaves kininogen substrate to produce vasoactive kinin peptides that have been implicated to play a role in the proliferation of vascular smooth muscle cells (VSMC). In order to explore potential roles of the kallikrein-kinin system in vascular biology, we evaluated the effects of adenovirus-mediated kallikrein gene delivery on neointima formation in balloon-injured rat artery. Infection of isolated rat aortic segments with adenovirus containing the human tissue kallikrein gene resulted in a time-dependent secretion of recombinant human tissue kallikrein, and significant increases in nitric oxide (NOx) and guanosine 3',5'-cyclic monophosphate (cGMP) levels post gene transfer. Human tissue kallikrein gene was delivered locally via adenoviral vectors into left common carotid artery after balloon angioplasty. Two weeks following gene transfer, we observed a 39% reduction in intima/media ratio at the injured vessel as compared to that of rats receiving control virus (n = 8, P < .01). Delivery of N(omega)-nitro-L-arginine methyl ester (L-NAME), a NOx synthase inhibitor via minipump for 2 weeks, blocked the protective effect and reversed the intima/media ratio to that of control rats (n = 5, P < .01). These results indicated that human tissue kallikrein gene delivery inhibits neointima formation via NO-cGMP signaling pathway. This study provides new insights into the role of the vascular kallikrein-kinin system and may have significant implications for gene therapy in treating occlusive vascular diseases.
Murakami
H
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Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425-2211, USA.
Miao
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RQ
Chao
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L
Chao
J
J
D000256:Adenoviridae / Q000235:genetics*; D000800:Angioplasty, Balloon; D000818:Animals; D001011:Aorta / Q000378:metabolism; D002339:Carotid Arteries / Q000254:growth & development / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007610:Kallikreins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D020840:Tissue Kallikreins / Q000235:genetics; D017539:Tunica Intima / Q000254:growth & development / Q000378:metabolism*
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D007610:Kallikreins; D020840:Tissue Kallikreins; D006152:Cyclic GMP