title: Assembly, activation, and signaling by kinin-forming proteins on human vascular smooth muscle cells.
abstract: Cardiovascular disease is the number one cause of death in the United States. Vascular smooth muscle cells (VSMC) are an important constituent of the vessel wall that can bring about pathological changes leading to vascular disease. Depending on the environment, the function of VSMC can deviate profoundly from its normal contractile role. Despite advances in research, the underlying mechanisms that activate VSMC toward vascular disease are poorly understood. For the first time, we have observed that factor XII and high-molecular-weight kininogen, constituents of the blood plasma, can bind to VSMC in a Zn2+-dependent manner. In the presence of prekallikrein, this assembly of factor XII and high-molecular-weight kininogen on VSMC leads to the activation of prekallikrein to kallikrein with a rapid formation of bradykinin. The amount of bradykinin in the culture medium then decreases, presumably because of the presence of a kininase activity. p44/42 mitogen-activated protein kinase is rapidly phosphorylated in response to in situ-generated or in vitro-added bradykinin and is inhibited by bradykinin antagonist HOE-140. Binding of factor XII to VSMC also results in a concentration-dependent phosphorylation of p44/42 mitogen-activated protein kinase. This early mitogenic signal, which is also implicated in atherogenesis, may change the metabolic and proliferative activity of VSMC, which are key steps in the progression of atherosclerosis.
authors.affiliation: Divisions of Pulmonary and Critical Care, Allergy and Clinical Immunology, Department of Medicine, Medical University of South Carolina, Charleston, 29425, USA.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Fernando
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Fernando
authors.forename: Yu
authors.initials: Y
authors.lastname: Fukuda
authors.forename: Allen P
authors.initials: AP
authors.lastname: Kaplan
mesh_terms: D001920:Bradykinin / Q000096:biosynthesis; D002478:Cells, Cultured; D005174:Factor XII / Q000378:metabolism; D006801:Humans; D019679:Kininogen, High-Molecular-Weight / Q000378:metabolism / Q000493:pharmacokinetics; D007705:Kinins / Q000096:biosynthesis*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009124:Muscle Proteins / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009994:Osmolar Concentration; D010766:Phosphorylation; D011288:Prekallikrein / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015032:Zinc / Q000494:pharmacology
chemical_list: D019679:Kininogen, High-Molecular-Weight; D007705:Kinins; D009124:Muscle Proteins; D005174:Factor XII; D011288:Prekallikrein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015032:Zinc; D001920:Bradykinin