Assembly, activation, and signaling by kinin-forming proteins on human vascular smooth muscle cells

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 prof...

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Bibliographic Details
Published in:	American journal of physiology. Heart and circulatory physiology Vol. 289; no. 1; p. H251
Main Authors:	Fernando, Anthony N, Fernando, Lawrence P, Fukuda, Yu, Kaplan, Allen P
Format:	Journal Article
Language:	English
Published:	United States 01-07-2005
Subjects:	Bradykinin - biosynthesis Cells, Cultured Factor XII - metabolism Humans Kininogen, High-Molecular-Weight - metabolism Kininogen, High-Molecular-Weight - pharmacokinetics Kinins - biosynthesis Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism Muscle Proteins - physiology Muscle, Smooth, Vascular - cytology Muscle, Smooth, Vascular - metabolism Myocytes, Smooth Muscle - metabolism Osmolar Concentration Phosphorylation Prekallikrein - metabolism Signal Transduction Time Factors Zinc - pharmacology
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Summary:	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.
ISSN:	0363-6135
DOI:	10.1152/ajpheart.00206.2004