Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue kallikrein cleaves kininogen substrate to produce vasoactive kinin peptides that have been implicated in the proliferation of vascular smooth muscle cells (VSMCs). To explore potential roles of the kallikrein-kinin system in vascular biology, we evaluated the effects of adenovirus-mediated human kallikrein gene delivery on the growth of primary cultured VSMCs and in balloon-injured rat artery in vivo. Kallikrein gene transfer into cultured rat VSMCs resulted in time-dependent secretion of recombinant human tissue kallikrein and inhibition of cell proliferation. Balloon angioplasty reduced endogenous rat tissue kallikrein mRNA and protein levels at the injured site. In rats that received adenovirus-mediated human kallikrein gene delivery, we observed a 39% reduction in intima/media ratio at the injured vessel after delivery compared with that of rats that received control virus (n=8, P<0.01). Icatibant, a specific bradykinin B(2) receptor antagonist, blocked the protective effect and reversed the intima/media ratio to that of the control rats (n=5, P<0.01). After gene delivery, human kallikrein mRNA was identified at the injured vessel and a 3-fold increase occurred in kininogenase activity. cAMP and cGMP levels in balloon-injured aorta increased significantly at 4, 7, and 14 days after kallikrein gene delivery, but icatibant abolished the increase. These results provide new insights into the role of the vascular kallikrein-kinin system and have significant implications for gene therapy to treat restenosis or atherosclerosis.
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PMID:Kallikrein gene delivery inhibits vascular smooth muscle cell growth and neointima formation in the rat artery after balloon angioplasty. 1045 35

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.
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PMID:Adenovirus-mediated human tissue kallikrein gene delivery inhibits neointima formation induced by interruption of blood flow in mice. 1084 58