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(Circulation Research. 2009;104:995.)
© 2009 American Heart Association, Inc.

Integrative Physiology

The Subendothelial Extracellular Matrix Modulates JNK Activation by Flow

Cornelia Hahn, A. Wayne Orr, John M. Sanders, Krishna A. Jhaveri, Martin Alexander Schwartz

From the Departments of Microbiology (C.H., M.A.S.), Cell Biology (M.A.S.), and Biomedical Engineering (M.A.S.); Robert M. Berne Cardiovascular Research Center (J.M.S., K.A.J., M.A.S.); and Mellon Urological Cancer Research Center (M.A.S.), University of Virginia, Charlottesville; and Department of Pathology (A.W.O.), Louisiana State University Health Sciences Center, Shreveport.

Correspondence to Martin Alexander Schwartz, Department of Microbiology, MR5, Room G111, University of Virginia, Charlottesville, VA 22908-0734. E-mail maschwartz{at}virginia.edu

Atherosclerosis begins as local inflammation of artery walls at sites of disturbed flow. JNK (c-Jun NH₂-terminal kinase) is thought to be among the major regulators of flow-dependent inflammatory gene expression in endothelial cells in atherosclerosis. We now show that JNK activation by both onset of laminar flow and long-term oscillatory flow is matrix-specific, with enhanced activation on fibronectin compared to basement membrane protein or collagen. Flow-induced JNK activation on fibronectin requires new integrin ligation and requires both the mitogen-activated protein kinase kinase MKK4 and p21-activated kinase. In vivo, JNK activation at sites of early atherogenesis correlates with the deposition of fibronectin. Inhibiting p21-activated kinase reduces JNK activation in atheroprone regions of the vasculature in vivo. These results identify JNK as a matrix-specific, flow-activated inflammatory event. Together with other studies, these data elucidate a network of matrix-specific pathways that determine inflammatory events in response to fluid shear stress.

Key Words: shear stress • atherosclerosis • JNK

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