Release of a new vascular permeability enhancing peptide from kininogens by human neutrophil elastase.
Stimulated neutrophils produced vascular permeability enhancing (VPE) activity in the presence of high molecular weight kininogen (HMWK), which was inhibited mainly by a neutrophil elastase (NE) inhibitor or a bradykinin (BK) B(2)-receptor antagonist. NE (>3 nM) generated VPE activity from kininogens at normal plasma concentrations with the smaller protein being several fold more responsive than the larger protein, through releasing a new VPE peptide (E-kinin), SLMKRPPGFSPFRSSRI. Synthetic E-kinin, SLMKRPPGFSPFRSS and SLMKRPPGFSPFR had VPE and blood pressure lowering activities, which were comparable to the activities of BK and completely inhibited by B(2)-receptor antagonists. Interestingly, E-kinin and SLMKRPPGFSPFRSS did not induce smooth muscle contraction. These results suggest that E-kinin formed in vivo may be processed at the carboxy-terminus to give a peptide that can bind to the B(2)-receptor. The molecular mechanism for neutrophil-associated VPE may be explained by excision of E-kinin from kininogens by NE, followed by further processing of the peptide.
Imamura
Takahisa
T
Division of Molecular Pathology, Department of Neuroscience and Immunology, Kumamoto University Graduate School of Medical Sciences, 2-2-1, Honjo, Kumamoto 860-0811, Japan. taka@kaiju.medic.kumamoto-u.ac.jp
Tanase
Sumio
S
Hayashi
Izumi
I
Potempa
Jan
J
Kozik
Andrzej
A
Travis
James
J
D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D002199:Capillary Permeability / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D019679:Kininogen, High-Molecular-Weight / Q000378:metabolism; D019728:Kininogen, Low-Molecular-Weight / Q000378:metabolism; D007704:Kininogens / Q000378:metabolism*; D007705:Kinins / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2
D065168:Bradykinin Receptor Antagonists; C459593:E kinin; D004791:Enzyme Inhibitors; D019679:Kininogen, High-Molecular-Weight; D019728:Kininogen, Low-Molecular-Weight; D007704:Kininogens; D007705:Kinins; D010455:Peptides; D043782:Receptor, Bradykinin B2; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019272:Leukocyte Elastase; D001920:Bradykinin