title: Deletion of murine kininogen gene 1 (mKng1) causes loss of plasma kininogen and delays thrombosis.
abstract: High-molecular-weight kininogen (HK) plays an important role in the assembly of the plasma kallikrein-kinin system. While the human genome contains a single copy of the kininogen gene, 3 copies exist in the rat (1 encoding K-kininogen and 2 encoding T-kininogen). Here, we confirm that the mouse genome contains 2 homologous kininogen genes, mKng1 and mKng2, and demonstrate that these genes are expressed in a tissue-specific manner. To determine the roles of these genes in murine development and physiology, we disrupted mKng1, which is expressed primarily in the liver. mKng1(-/-) mice were viable, but lacked plasma HK and low-molecular-weight kininogen (LK), as well as DeltamHK-D5, a novel kininogen isoform that lacks kininogen domain 5. Moreover, despite normal tail vein bleeding times, mKng1(-/-) mice displayed a significantly prolonged time to carotid artery occlusion following Rose Bengal administration and laser-induced arterial injury. These results suggest that a single gene, mKng1, is responsible for production of plasma kininogen, and that plasma HK contributes to induced arterial thrombosis in mice.
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Merkulov
authors.forename: Wan-Ming
authors.initials: WM
authors.lastname: Zhang
authors.forename: Anton A
authors.initials: AA
authors.lastname: Komar
authors.forename: Alvin H
authors.initials: AH
authors.lastname: Schmaier
authors.forename: Ellen
authors.initials: E
authors.lastname: Barnes
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xincheng
authors.initials: X
authors.lastname: Lu
authors.forename: Takayuki
authors.initials: T
authors.lastname: Iwaki
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Castellino
authors.forename: Guangbin
authors.initials: G
authors.lastname: Luo
authors.forename: Keith R
authors.initials: KR
authors.lastname: McCrae
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001920:Bradykinin / Q000097:blood; D017353:Gene Deletion; D005822:Genetic Vectors / Q000235:genetics; D006720:Homozygote; D007704:Kininogens / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010949:Plasma / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D016415:Sequence Alignment; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D007704:Kininogens; D012333:RNA, Messenger; D001920:Bradykinin