The High Mobility Group (Hmg) Boxes of the Nuclear Protein Hmg1 Induce Chemotaxis and Cytoskeleton Reorganization in Rat Smooth Muscle Cells

Bernard Degryse^a, Tiziana Bonaldi^b, Paola Scaffidi^b, Susanne Müller^b, Massimo Resnati^b, Francesca Sanvito^b, Gianluigi Arrigoni^b, , and Marco E. Bianchi^b

^a Department of Genetics and Microbiology, University of Milan, 20133 Milan, Italy
^b Department of Biological and Technological Research, San Raffaele Scientific Institute, 20132 Milan, Italy
Department of Vascular Biology/VB-3, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.(858) 784-7353(858) 784-7153

degryse{at}scripps.edu

Abstract: HMG1 (high mobility group 1) is a ubiquitous and abundant chromatin component. However, HMG1 can be secreted by activated macrophages and monocytes, and can act as a mediator of inflammation and endotoxic lethality. Here we document a role of extracellular HMG1 in cell migration. HMG1 (and its individual DNA-binding domains) stimulated migration of rat smooth muscle cells in chemotaxis, chemokinesis, and wound healing assays. HMG1 induced rapid and transient changes of cell shape, and actin cytoskeleton reorganization leading to an elongated polarized morphology typical of motile cells. These effects were inhibited by antibodies directed against the receptor of advanced glycation endproducts, indicating that the receptor of advanced glycation endproducts is the receptor mediating the HMG1-dependent migratory responses. Pertussis toxin and the mitogen-activated protein kinase kinase inhibitor PD98059 also blocked HMG1-induced rat smooth muscle cell migration, suggesting that a G_i/o protein and mitogen-activated protein kinases are required for the HMG1 signaling pathway. We also show that HMG1 can be released by damage or necrosis of a variety of cell types, including endothelial cells. Thus, HMG1 has all the hallmarks of a molecule that can promote atherosclerosis and restenosis after vascular damage.

Key Words: atherosclerosis • chemotaxis • high mobility group 1 • receptor of advanced glycation endproducts • smooth muscle cells

Abbreviations used in this paper: HMG1, high mobility group 1; HUVEC, human umbilical vein endothelial cells; MAP, mitogen-activated protein; PT, Bordetella pertussis toxin; RAGE, receptor for advanced glycation endproducts; RSMC, rat smooth muscle cells; SMC, smooth muscle cells.

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